01-Pediatrics in Review-January 2008

Article
hematology/oncology
Neutropenia in Pediatric
Practice
George B. Segel, MD,* Jill
S. Halterman, MD, MPH
Author Disclosure
Drs Segel and
Halterman did not
Objectives
After completing this article, readers should be able to:
1. Describe when a patient has true neutropenia, understanding the variation with age
and ethnic background.
2. Know the relative risk of infection at various values of the absolute neutrophil count.
3. Discuss the differences between inherited and acquired causes of neutropenia.
4. List the initial studies to evaluate patients who have neutropenia.
disclose any financial

relationships relevant
to this article.
Introduction
The significance of neutropenia is a common query to hematology specialists from primary
care physicians. Severe neutropenia is defined as an absolute neutrophil count (ANC) of
fewer than 500/mcL (0.5109/L) and is a common and expected complication of
chemotherapy for childhood neoplasms. This article considers those patients who have
neutropenia unrelated to chemotherapy toxicity. This type of neutropenia may be noted
when a complete blood count (CBC) is performed in a sick newborn, a febrile child, a child
taking chronic medication, or as part of a routine evaluation. Severe hereditary conditions
such as Kostmann syndrome and certain immunodeficiency syndromes associated with
neutropenia are rare, perhaps 1 per 100,000, and are more likely to present in neonates and
infants, although acquired conditions such as immune neutropenia and neutropenia
related to infection also occur in this age group. A mild-to-moderate decrease in the ANC
(percent neutrophils times the total white count) frequently is seen in viral illness or related
to medication use as well as in some healthy persons of African ancestry. A number of
inherited conditions associated with neutropenia are associated with other congenital
anomalies such as dysplastic thumbs in Fanconi anemia, albinism in Chediak-Higashi
syndrome, and dwarfism in the cartilage hair or Shwachman-Diamond syndromes.
When to Order a CBC

A CBC is not ordered routinely for well children examined in the pediatricians office or
when children present with common febrile illnesses such as upper respiratory tract
infections or otitis media. A CBC is warranted if clinical findings suggest a more severe
bacterial infection. Such clinical findings include, but are not limited to, recurrent
infections; prolonged or extreme fever (103F [39.5C]); the spreading of localized
bacterial infection; infection of the lung, peritoneum, genitourinary tract, or central
nervous system; and suspicion of chronic inflammatory disease, immunodeficiency, or
malignancy. A CBC also may be warranted if a patients clinical course is atypical,
prolonged, or complicated by signs and symptoms suggesting the development of a
secondary bacterial infection.
Normal Values for the ANC and the Definition of Neutropenia

Normal values for the ANC vary by age, particularly during the first weeks after birth.
Normal leukocyte counts and ANCs for children from birth to age 21 years are shown in
Table 1. The ANC range is shown for each age, as well. The lower limit of normal is
6,000/mcL (6.0109/L) during the first 24 hours after birth, 5,000/mcL (5.0109/L)
for the first week, 1,500/mcL (1.5109/L) during the second week, 1,000/mcL
*Professor, Department of Pediatrics, Division of Hematology Oncology.
Associate Professor of Pediatrics, Division of General Pediatrics, University of Rochester School of Medicine & Dentistry,
Rochester, NY.
12 Pediatrics in Review Vol.29 No.1 January 2008
hematology/oncology
Table 1.
neutropenia
Normal Blood Leukocyte Counts*

Total Leukocytes
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Age
Mean
(Range)
Mean
(Range)
Mean
(Range)
Mean
Mean
Birth
12 h
24 h
1 wk
2 wk
1 mo
6 mo
1y
2y
4y
6y
8y
10 y
16 y
21 y
18.1
22.8
18.9
12.2
11.4
10.8
11.9
11.4
10.6
9.1
8.5
8.3
8.1
7.8
7.4
(9.0 to 30.0)
(13.0 to 38.0)
(9.4 to 34.0)
(5.0 to 21.0)
(5.0 to 20.0)
(5.0 to 19.5)
(6.0 to 17.5)
(6.0 to 17.5)
(6.0 to 17.0)
(5.5 to 15.5)
(5.0 to 14.5)
(4.5 to 13.5)
(4.5 to 13.5)
(4.5 to 13.0)
(4.5 to 11.0)
11.0
15.5
11.5
5.5
4.5
3.8
3.8
3.5
3.5
3.8
4.3
4.4
4.4
4.4
4.4
(6.0 to 26.0)
(6.0 to 28.0)
(5.0 to 21.0)
(1.5 to 10.0)
(1.0 to 9.5)
(1.0 to 9.0)
(1.0 to 8.5)
(1.5 to 8.5)
(1.5 to 8.5)
(1.5 to 8.5)
(1.5 to 8.0)
(1.5 to 8.0)
(1.8 to 8.0)
(1.8 to 8.0)
(1.8 to 7.7)
61
68
61
45
40
35
32
31
33
42
51
53
54
57
59
5.5
5.5
5.8
5.0
5.5
6.0
7.3
7.0
6.3
4.5
3.5
3.3
3.1
2.8
2.5
(2.0 to 11.0)
(2.0 to 11.0)
(2.0 to 11.5)
(2.0 to 17.0)
(2.0 to 17.0)
(2.5 to 16.5)
(4.0 to 13.5)
(4.0 to 10.5)
(3.0 to 9.5)
(2.0 to 8.0)
(1.5 to 7.0)
(1.5 to 6.8)
(1.5 to 6.5)
(1.2 to 5.2)
(1.0 to 4.8)
31
24
31
41
48
56
61
61
59
50
42
39
38
35
34
1.1
1.2
1.1
1.1
1.0
0.7
0.6
0.6
0.5
0.5
0.4
0.4
0.4
0.4
0.3
6
5
6
9
9
7
5
5
5
5
5
4
4
5
4
0.4
0.5
0.5
0.5
0.4
0.3
0.3
0.3
0.3
0.3
0.2
0.2
0.2
0.2
0.2
2
2
2
4
3
3
3
3
3
3
3
2
2
3
3
*Numbers of leukocytes are in thousands/mcL (109/L), ranges are estimates of 95% confidence limits, and percentages refer to differential counts.
Neutrophils include band cells at all ages and a small number of metamyelocytes and myelocytes in the first few postnatal days.
From Dallman PR. Blood and blood-forming tissues. In: Rudolph AM, ed. Rudolphs Pediatrics. 16th ed. New York, NY: Appleton-Century-Crofts;
1977:1178, with permission.
(1.0109/L) between 2 weeks and 1 year of age, 1,500/

mcL (1.5109/L) from ages 1 year through 10 years,
and 1,800/mcL (1.8109/L) thereafter. However,
most reports use 1,500/mcL (1.5109/L) as the lower
limit of normal for white adults. Adults and children of
African extraction may have ANCs between 1,000 and
1,500/mcL (1.0 and 1.5109/L), which overlaps the
values observed in patients who have mild neutropenia. We estimate from the data available that at least 3%
to 5% of persons of African ancestry have ANCs below
1,500/mcL (1/5109/L).
Risk Assessment
For patients older than 1 year of age, mild neutropenia is
defined as an ANC of 1,000 to 1,500/mcL (1.0 to
1.5109/L), moderate neutropenia as an ANC of
500 to 1,000/mcL (0.5 to 1.0109/L), and severe
neutropenia as an ANC of less than 500/mcL
(0.5109/L). Usually, patients are highly susceptible to
bacterial infection if the ANC is less than 500/mcL
(0.5109/L), with the risk of infection greatest at the
lowest ANCs. Increased infection risk also is related to
longer durations of neutropenia and is highest if the
neutrophil count remains low without recovery. If neutrophils can be mobilized to respond, infection is less
likely to occur, as can be seen in immune neutropenia, a
condition in which there is myeloid hyperplasia and
heightened neutrophil production. Although serious
bacterial infections are observed when the ANC is between 500 and 1,000/mcL (0.5 and 1.0109/L), they
are much less frequent or severe. There is little or no
heightened infectious risk if the ANC is greater than
1,000/mcL (1.0109/L).
Pyogenic Infections Associated With

Neutropenia
Moderate-to-severe neutropenia may portend an inadequate neutrophil response to bacterial infection. The
clinical signs of neutropenia may include ulcerations of
the oral mucosa or gingival inflammation. Otitis media,
skin infections that include cellulitis and pustules, adenitis, pneumonia, and bacterial sepsis may occur. The
source of the infection may be the childs own skin or
bowel flora. Perianal infection and ischiorectal fossa abscesses sometimes are seen. The most common offending
organisms are Staphylococcus aureus and the gramnegative bacteria (see section on fever and neutropenia).
Initial Evaluation of the Patient Who Has

Neutropenia
The initial evaluation (Table 2) should include a history
and physical examination. It is critical to know whether
the child has had recurrent bacterial infections, whether
there is a family history of neutropenia or infection, and
after physical examination, whether there are any associated congenital anomalies that suggest an inherited synPediatrics in Review Vol.29 No.1 January 2008 13
hematology/oncology
neutropenia
Initial Evaluation for

Patients Who Have
Neutropenia
Table 2.
History
History of underlying disease, congenital anomalies,

medication exposure, or recent infection or mouth
ulceration
Other family members who have neutropenia and
serious infections, hospitalizations, or blood diseases
Physical Examination
Short stature, malnutrition, skeletal abnormalities

Abnormal skin pigmentation, dystrophic nails,
leukoplakia, warts, albinism, fine hair, eczema, skin
infections, adenopathy, and organomegaly
CBC With Differential Count and Reticulocyte

Percentage
Confirm the finding of neutropenia, evaluate

neutrophil morphology, and assess whether red cell
production is increased or decreased
If the neutropenia resolves and is recurrent, repeat
two to three times per week for 6 weeks
Other Laboratory Tests
Blood smear
Coombs test (direct antiglobulin test) for associated
hemolytic anemia
Immunoglobulins (IgA, IgG, IgM)
Serology (Epstein-Barr virus, cytomegalovirus,
respiratory syncytial virus, parvovirus, etc, as
indicated clinically)
Antineutrophil antibodies
drome. Mouth ulcers may occur in association with

neutropenia, and the presence of gingivitis is a good
indicator that the patient cannot mobilize adequate neutrophils and, thus, may be susceptible to severe infection.
If neutropenia is suspected, it is important to determine if
the patient has isolated neutropenia or neutropenia associated with anemia or thrombocytopenia. The clinical
implication of deficits of more than one cell type is
different from that of an isolated neutropenia. Anemia or
thrombocytopenia in conjunction with neutropenia often reflects a more generalized marrow failure syndrome
such as aplastic anemia or a marrow infiltrative process
such as leukemia. The neutropenia must be confirmed by
repeating the CBC to avoid an extensive evaluation due
to a laboratory error.
It is reasonable to observe the patient who has a viral
illness and mild-to-moderate neutropenia and otherwise
appears well. If the neutropenia persists or progresses

after 1 to 2 weeks, additional evaluation is necessary. If
the neutropenia is recurrent, obtaining blood counts two
to three times per week for several weeks can establish
any cycles of neutropenia. If additional evaluation is
warranted, the presence of antineutrophil antibodies
suggests immune neutropenia, and quantifying immunoglobulins, including IgG, IgA, and IgM, and the
distribution of lymphocyte subsets may indicate an underlying immunodeficiency syndrome. In addition,
screening tests for systemic lupus erythematosus, including an antinuclear antibody titer and anti-doublestranded DNA, can be helpful. If a patient has severe
neutropenia, referral to a hematologist is necessary. If
severe congenital neutropenia is suspected, assessing for
the HAX1 mutation for Kostmann disease and ELA2
mutation for dominant or sporadic severe congenital
neutropenia is indicated. A detailed presentation of the
potential laboratory evaluation by hematology is shown
in Table 3.
Acquired Neutropenia
Infection
When evaluating the child who has neutropenia, the
acquired neutropenias are considered first because of
their greater frequency (Table 4). The most common
underlying cause for mild-to-moderate neutropenia is
transient marrow suppression due to a variety of viral
infections. Neutropenia is seen in patients who have
Epstein-Barr virus, respiratory syncytial virus, influenza A
and B, hepatitis, and human herpesvirus 6 infections
as well as the exanthems (to which most children are
immunized), including varicella, rubella, and rubeola.
Neutropenia occurs often during the first few days of the
viral illness and persists for 3 to 8 days. Severe bacterial
infection also may cause neutropenia rather than neutrophilia, which can be transient if the bacterial infection is
treated effectively. Other bacterial or rickettsial diseases
such as typhoid fever, tuberculosis, and Rocky Mountain
spotted fever may cause neutropenia.
Drug-induced
A variety of medications (Table 5), including antibiotics,
anticonvulsants, and anti-inflammatory agents, have
been associated with neutropenia, a frequent reason for
referral to hematology. The dilemma is how to treat the
patient who requires the particular medication that is
causing a potentially dangerous adverse effect. If the
drug-induced neutropenia is idiosyncratic, its severity
and persistence may be impossible to predict, and it is
difficult to avoid discontinuing the drug. A similar situ-
hematology/oncology
Table 3.
neutropenia
Detailed Laboratory Evaluation of Neutropenia
Test
Findings
CBC and Differential Count

Reticulocyte % (Index)
ANC less than lower limit for age (Table 1) anemia and thrombocytopenia
Increased if RBC destruction, as in Evans syndrome (or bleeding)
Decreased in marrow failure syndromes
Confirms decreased ANC
Morphologic abnormalities of neutrophils, as in Chediak-Higashi syndrome
Associated RBC or platelet findings
Detects antibodies to RBC, as in Evans syndrome or systemic lupus
erythematosus
Screen for systemic lupus erythematosus
May be found in alloimmune or autoimmune neutropenia
Screen for underlying immunodeficiency
IgG and IgA may be decreased and IgM elevated
Decreased T, B, or NK cells in underlying immunodeficiency
May show no maturation beyond the promyelocyte stage in severe
congenital neutropenia; myeloid hyperplasia with few or no bands or
mature neutrophils in immune neutropenia
Cytogenetics may reveal a neoplastic clone, as in leukemia
Specific for genetic diagnosissee Table 6 for specific genes
Blood Smear
Coombs Test (Direct Antiglobulin Test)
ANA Anti-double-stranded DNA
Antineutrophil Antibody
IgG, IgA, IgM
Lymphocyte Subtypes
Marrow Examination
DNA Analysis (HAX1, ELA2, Gfil)

(FANC, DKC, RPS19)
Serum Trypsinogen, Other Stool Fat
Nutritional
Low serum trypsinogen and elevated stool fat found in ShwachmanDiamond syndrome
Serum vitamin B12, RBC, and serum folic acid
ANAantinuclear antibody, ANCabsolute neutrophil count, CBCcomplete blood count, RBCred blood cell.
ation exists for drug-induced immune neutropenia. If the

drug acts as a hapten, leading to production of an antibody, the ANC should improve within 1 to 2 weeks after
cessation of drug administration. On the other hand, if
the neutropenia is mild, it may be dose-related, and drug
administration could be titrated to permit continued use.
Immune
Neonatal alloimmune neutropenia results from the transfer of fetal cells to the maternal circulation, causing the
mother to produce antibody to fetal antigens not present
on her own cells in a manner similar to Rh disease.
A variety of neutrophil-specific antigens have been identified and are designated HNA-1a (NA1), HNA-1b
(NA2), HNA-2a (NB1), HNA-3a (5b), HNA-4a
(MART), and HNA-5a (OND). Because the half-life of
IgG is approximately 5 to 6 weeks, alloimmune neutropenia usually disappears after age 2 to 3 months. If
infections are associated with the neutropenia, granulocyte colony-stimulating factor (G-CSF) may be used to
stimulate a heightened neutrophil count.
Passive transfer of maternal antibody also may cause
neonatal neutropenia. Pregnant women who have either
primary immune neutropenia or immune neutropenia
due to a disease such as lupus may transfer IgG antineu-
trophil antibodies passively to the developing fetus. This

type of neonatal neutropenia also is transient.
Primary autoimmune neutropenia of infancy and
childhood may be the cause of chronic neutropenia. The
diagnosis may be established in most patients with the
demonstration of antineutrophil antibodies by leukoagglutination or immunofluorescence. These antibodies
may develop as a result of molecular mimicry, wherein
an epitope on the surface of an infecting virus stimulates
production of an antibody that then cross-reacts with a
similar antigen on the surface of the neutrophil, leading
to neutrophil destruction. Such antibodies often are directed against NA1. Marrow examination reveals myeloid hyperplasia but with few mature neutrophils (pictures of normal bone marrow and marrow in immune
neutropenia are available in the online edition of this
issue of Pediatrics in Review [www.pedsinreview.org]).
The neutropenia may be profound, and the child may
develop ear, pulmonary, skin, or other infections. Such
infections are treated primarily with antibiotics. However, glucocorticoids such as prednisone may suppress
the immune destruction of neutrophils, and more recently, G-CSF has been used to heighten neutrophil
production to overcome the antibody-induced destruction. The initial dose of prednisone usually is 2 mg/kg
Pediatrics in Review Vol.29 No.1 January 2008 15
hematology/oncology
Table 4.
neutropenia
Acquired Neutropenia
Condition
Pathogenesis
Occurrence
Associated Findings
Infection
Viral marrow suppression or

viral-induced immune
neutropenia
Bacterial sepsis-endotoxin
suppression
Direct marrow suppression
Immune destruction
Primary (molecular
mimicry)
Secondary (SLE, Evans
syndrome)
Alloimmunematernal
sensitization
Due to maternal
autoimmune neutropenia
Ineffective or decreased
production
Common
EBV/parvovirus/HHV6 and other viruses
Less common
Severe infection
Common
Less common
Common
Underlying condition
Drug-induced
Autoimmune
Newborn Immune
Chronic Idiopathic
Monocytosis common
Rare
Antigen difference in newborn and

mother
Maternal neutropenia
Common
Consider also familial benign

neutropenia
Often asymptomatic
Mild neutropenia
Enlarged spleenmany causes
Marrow megaloblastic
Sequestration
Hypersplenism
Common if spleen is enlarged
Nutritional
Vitamin B12 or folic acid

deficiency
Impaired DNA processing
Rare in children
Hypersegmented neutrophils
EBVEpstein-Barr virus, HHVhuman herpesvirus, SLEsystemic lupus erythematosus.
per day administered orally in two divided doses, and the

initial dose of G-CSF is 5 mcg/kg administered subcutaneously once a day. These therapies usually are administered under the guidance of a pediatric hematologist.
Secondary autoimmune neutropenia more often affects adults and is seen in systemic autoimmune diseases,
such as systemic lupus erythematosus, rheumatoid arthritis (Felty syndrome), or systemic sclerosis; in certain
infections, such as those due to human immunodeficiency virus, parvovirus B19, or Helicobacter pylori; or in
drug-induced neutropenia. Secondary autoimmune neutropenia also has been reported in association with Wilms
tumor and Hodgkin disease. Treatment of secondary
neutropenias is directed toward the primary disease. Administration of G-CSF may be considered if the neutropenia is severe and protracted.
Chronic Idiopathic
Chronic idiopathic neutropenia likely represents a variety
of disorders and is not well characterized. Some of the
patients classified as having chronic idiopathic neutropenia actually may have immune neutropenia or familial
benign neutropenia. The idiopathic diagnosis may be
considered when other known causes have been eliminated. The clinical severity appears to be related to the
severity of neutropenia, and the marrow findings are not

consistent. Ineffective or decreased production of neutrophils may be seen in this condition. Many hematologists watch patients whose conditions appear truly idiopathic and whose neutropenia is mild and not associated
with an increase in infections, keeping the evaluation to a
minimum rather than pursuing a more extensive evaluation that often yields nothing. When therapy is indicated,
glucocorticoids and G-CSF have been used.
Sequestration
Splenomegaly and hypersplenism from any cause may
result in mild neutropenia (1,000 to 1,500/mcL [1.0 to
1.5109/L]) due to sequestration. Enlarged spleens
may be present in patients who have chronic hemolytic
anemias, liver disease, or portal hypertension and in
metabolic disorders such as Gaucher disease. These conditions also may result in anemia and thrombocytopenia.
Results of the marrow examination are normal or show
mild hyperplasia of all elements. Usually, this problem
does not require treatment unless the cytopenias are
profound or management of the underlying condition
requires treatment. In some cases, splenectomy is necessary.
hematology/oncology
Table 5.
neutropenia
Partial List of Drugs Associated With Idiosyncratic Neutropenia

Possible Mechanism
Drug
Analgesics/Anti-inflammatory Agents
Aminopyrine
Ibuprofen
Indomethacin
Phenylbutazone
Antibiotics
Chloramphenicol
Penicillins
Sulfonamides
Anticonvulsants
Phenytoin
Carbamazepine
Antithyroid Agents
Propylthiouracil
Cardiovascular Agents
Hydralazine
Procainamide
Quinidine
Hypoglycemic Agents
Chlorpropamide
Tranquilizers
Chlorpromazine
Phenothiazines
Other
Cimetidine, ranitidine
Levamisole
Direct
Suppression
Metabolite
Suppression
Immune
Destruction
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Reproduced from Dinauer MC. The phagocyte system and disorders of granulopoiesis and granulocyte function. In: Nathan DG, Orkin SH, Look AT,
Ginsburg D, eds Nathan and Oskis Hematology of Infancy and Childhood. 6th ed. Philadelphia, Pa: WB Saunders Company; 2003:9231010 with permission.
Nutritional Deficiency
Both vitamin B12 and folic acid deficiency may result in
ineffective hematopoiesis with megaloblastic erythropoiesis. Patients who develop megaloblastic anemia generally are adults. In addition to megaloblastic anemia, the
impairment in DNA processing may result in neutropenia. Neutrophil nuclear maturation is impaired, leading
to hypersegmentation of the neutrophil nuclei in the
blood as well as ineffective marrow proliferation and
maturation. Treatment involves replacement of the deficient factor.
Inherited Neutropenia (Table 6)

Severe Congenital
Severe congenital neutropenia may present as early as
infancy with umbilical infection, pyoderma, oral ulcers,
pulmonary infections, or perineal infections of the labia
or perirectal area. The ANC is less than 500/mcL
(0.5109/L) and often less than 200/mcL (0.2109/
L). Severe congenital neutropenia may be inherited as an
autosomal recessive condition (Kostmann syndrome) involving mutations in the HAX1 gene that is involved in
signal transduction. It also may be inherited as an autosomal dominant condition, with mutations in the neutrophil elastase gene (ELA2) or, more rarely, in the GFI1
gene that targets ELA2. It has been suggested that such
gene mutations result in accelerated apoptosis of myeloid
precursors. Examination of the marrow reveals an arrest
at the promyelocyte stage of development (a picture of
bone marrow in severe congenital neutropenia is available in the online edition of this issue of Pediatrics in
Review [www.pedsinreview.org]). Few or no myelocytes, metamyelocytes, bands, or mature neutrophils are
seen, and there may be an associated monocytosis and
eosinophilia in the blood. Affected patients have a very
high risk of developing a myelodysplastic syndrome or
acute myelogenous leukemia, a consequence that has
become more evident as patients live longer with treatment using G-CSF. Table 7 describes G-CSF administration.
hematology/oncology
Table 6.
neutropenia
Inherited Neutropenia
Condition
Inheritance
Pathogenesis
Severe Congenital
(Kostmann)
AR
Severe Congenital
AD and
sporadic
Cyclic
AD
Shwachman-Diamond
Syndrome
AR
Familial Benign
AD
Rare (1/1 to 200,000) ANC <500/mcL (0.5109/L)

HAX1 mutations
causing disturbed
Leukemia risk of 15% to 20%
regulation of myeloid
homeostasis
Marrow arrest at the
promyelocyte stage
ELA2 mutations on the Rare (1/1 to 200,000) ANC <500/mcL (0.5109/L)
face of the molecule
Leukemia risk of 5% to10%
opposite the active
site causing
accelerated apoptosis
2 T and B cells
GFI1 mutations target Two families
Marrow has immature myeloid
ELA2
cells
ELA2 mutations
0.5 to 1/106
21-day cycle with fever and
clustering near the
mouth ulcers
active site of the
molecule
1/50,000
Pancreatic exocrine
SDS gene conversion
insufficiency, short stature,
from the pseudogene,
metaphyseal dysplasia,
resulting in failure of
marrow failure, and leukemia
neutrophil production
risk (15%)
Defect in RNA
processing
Decreased CD34 cells
Decreased marrow
Common
Africans and Yemenite Jews
release
Periodontal disease
Marrow Failure Syndromes:

Fanconi
AR
Dyskeratosis Congenita
Blackfan Diamond
Syndrome
Dysgammaglobulinemia or
Hyper-IgM
WHIM Syndrome and

Myelokathexis
Occurrence
Gene (FANC) defects in 1/106

DNA repair
Usually XR
DKC1 (TERC or TERT in
(also AR and AD) mutations
AD)
Telomerase defect,
ribosomal dysfunction
Sporadic 75% RPS19 mutations that
AR and AD
affect a ribosomal
protein in 25% of
families
? Mechanism of
erythropoietic failure
Many patients respond
to glucocorticoids
XR (also AR) CD40 ligand mutations
? Immune neutropenia,
but antineutrophil
antibody is negative
AD (also ?AR) Imbalance in pro- and Case reports
anti-apoptosis
Defect in CXCR4
receptor leading to
failure of neutrophils
to leave the marrow
Associated Findings
Dysplastic thumbs,
pancytopenia, other
anomalies
Abnormal skin pigmentation,
leukoplakia, dystrophic nails
Erythroid failure syndrome
Neutropenia in 25% to 40%
Thumb and craniofacial
anomalies
Increased RBC adenosine
deaminase
Leukemia risk of 2% to 3%
2IgG, 2IgA, 1IgM
May have immune
thrombocytopenia and
anemia
Neutropenia only seen in XR
Warts, hypogammaglobulinemia,
infections, and myelokathexis
(WHIM)
hematology/oncology
Table 6.
neutropenia
Inherited Neutropenia Continued
Condition
Inheritance
Chediak-Higashi Syndrome AR
Reticular Dysgenesis
AR
Cartilage Hair
AR
Metabolic Glycogen
AR
Storage Disease 1b
(also aminoacidopathies)
Griscelli Syndrome Type 2
AR
Barth Syndrome
XR
Wiscott-Aldrich Syndrome XR
Selective IgA Deficiency
Unknown or
multifactorial
Pathogenesis
Occurrence
Rare
CHS1 ?defect in
lysosomal fission
Abnormal protein
trafficking
Decreased neutrophil
chemotaxis,
degranulation,
and killing
Stem cell failure in
Rare
lymphoid and
myeloid development
RMRP mutations
Rare
Defect in a ribonuclear
protein ribonuclease
G6PT1 mutations
(glucose-6phosphate
translocase) in 1b
RAB27A mutations
Impaired lytic granule
release
1/105 live births
Rare
TAZ mutation on the X Rare

chromosome
Cardiolipin defect
Mutations in the Cdc42 1 to 10/106
binding site in the
WASP gene
Results in X-linked
neutropenia
Unknown
Common (1/600)
Associated Findings
2NK and T-cell function
Albinism
Neurologic damage and giant
lysosomes
Severe combined
immunodeficiency with
neutropenia
Fine hair, short-limbed,
dwarfism, lymphopenia,
2CD4 and 2CD8 cells
Infections, particularly varicella
zoster
Hypoglycemia, dyslipidemia,
1uric acid, 1lactic acid, and
neutropenia in most patients
Partial albinism, neutropenia,
infections, and
thrombocytopenia with
hemophagocytosis and T-cell
defect
Dilated cardiomyopathy
Skeletal myopathy
Mitochondrial abnormalities
Impaired lymphoid development
and maturation of monocytes
Associated with eczema,
thrombocytopenia, and
immune deficiency
Infections of the upper and
lower respiratory tracts in
one third of patients
ARautosomal recessive, ADautosomal dominant, ANCabsolute neutrophil count, Igimmunoglobulin, NKnatural killer, RBCred blood cell,
XRX-linked recessive.
Cyclic
Cyclic neutropenia is characterized by approximately
21-day cycles of changing neutrophil counts, with neutropenia spanning 3 to 6 days. The nadir of the neutrophil count may be in the severe range. Fever and oral
ulcerations usually are seen during the nadir. Patients
also may develop gingivitis, pharyngitis, and skin infections. However, by the time the patient comes to medical
attention, the neutrophil count may be recovering.
Therefore, diagnosing cyclic neutropenia may require
obtaining blood counts two to three times per week for
4 to 6 weeks in an effort to observe the periodicity of the
cycle.
More serious infections include pneumonia, necrotizing enterocolitis with peritonitis, and Escherichia coli or
Clostridium sepsis. Marrow findings reflect the state of
neutropenia. Prior to the ANC nadir, the marrow may
resemble that associated with severe congenital neutropenia before proceeding to a recovery phase. The periodicity of marrow activity also may be seen in the erythroid series. As in severe congenital neutropenia,
mutations occur in the ELA2 gene, but at different
locations (Table 6). Also, there does not appear to be an
increased risk of myelodysplasia or acute myelogenous
leukemia. Prophylactic G-CSF has been recommended
to prevent severe symptoms at the nadir of the cycle.
hematology/oncology
Table 7.
neutropenia
Treatment of Neutropenia
Granulocyte Colony-stimulating
Factor
Glucocorticoids
Nutritional
Splenectomy
Medication Revision
Antibiotics
Granulocyte Transfusion
Initially 5 mcg/kg per day subcutaneously

If no response after 1 wk, the dose may be doubled repeatedly up to 100 mcg/kg per day
Prednisone 2 mg/kg per day PO for immune neutropenia
Vitamin B12 1,000 mcg each week for 5 to 6 wk, then q 1 mo subcutaneously if B12deficient
Folic acid 1 mg/d PO
Prior immunization to encapsulated bacterial (pneumococcus, Haemophilus influenzae
type b, meningococcus) required
Prophylactic penicillin after splenectomy 125 mg bid <age 5 y; 250 mg bid >age 5 y
If possible, reduce dosage or discontinue any medications associated with neutropenia
As appropriate for patients age, type and location of infection, and if possible, culture
results
May be useful in invasive bacterial or fungal infections for patients who have severe
neutropenia (ANC <500/mcL [0.5109/L]) who are not responding to antibiotics
Shwachman-Diamond Syndrome
Patients who have Shwachman-Diamond syndrome usually have a mild-to-moderate degree of neutropenia in
association with exocrine pancreatic insufficiency, short
stature, metaphyseal dysplasia, marrow failure, and the
risk of myelodysplasia and acute myelogenous leukemia.
A defect in RNA processing leads to a failure of neutrophil development. Malabsorption and failure to thrive
are common problems, and affected patients may develop infections because of the neutropenia and a possible defect in chemotaxis. G-CSF has been used when the
neutropenia is symptomatic; pancreatic replacement
therapy is required.
Marrow Failure Syndromes

FANCONI ANEMIA. Fanconi anemia is characterized
by pancytopenia (with all cell lines affected). It presents
most commonly in the second half of the first decade of
life, and thrombocytopenia may precede the development of anemia and neutropenia. The marrow is hypoplastic and resembles aplastic anemia. The disease is
characterized by a defect in DNA repair leading to extensive chromosomal breakage, and there is hypersensitivity
to DNA cross-linking agents such as diepoxybutane in
vitro. Affected patients have mutations in the FANC
genes, primarily in FANC A, C, and G. Clinically, patients may have short stature; dysplastic thumbs; or heart,
kidney, or eye abnormalities. They have a nearly 10% risk
of developing a myelodysplastic syndrome or acute myelogenous leukemia. The pancytopenia may respond to
androgen treatment, which is particularly difficult to use
in young women. G-CSF and other cytokines may be
effective, but their efficacy may not be sustained. The
only curative treatment for Fanconi anemia is stem cell
transplantation.
DYSKERATOSIS CONGENITA (ZINSSER-ENGMAN-COLE

SYNDROME). This abnormality results from a mutation
in the DKC1 gene that encodes dyskerin, a component
of the telomerase complex, which is responsible for the
elongation of DNA. Affected patients exhibit abnormal
skin pigmentation, leukoplakia, and dystrophic nails. The
skin and mucosal lesions appear in the second decade,
and marrow failure develops in early adulthood. Patients
may present with isolated neutropenia, but more often,
all cell lines are affected. Hematopoietic growth factors,
such as G-CSF, may be useful in treating the neutropenia. Abnormalities of T-helper cells and dysgammaglobulinemia may contribute to a susceptibility to infection in some patients.
Syndromes Associated With Neutropenia and

Immunodeficiency
A variety of syndromes include neutropenia and abnormalities in T, B, or natural killer cell function. The
combined problem of neutropenia and immunodeficiency makes patients who have these syndromes more
susceptible to infectious complications. One condition is
the hyper-IgM syndrome, in which concentrations of
IgG and IgA are diminished and IgM is heightened. The
nature of the neutropenia is not known, but may be
immune in origin, although antineutrophil antibodies
are negative. Other syndromes associated with neutropenia and immunodeficiency are listed in Table 6; their
associated findings are particularly important for defining
these rare syndromes.
Fever and Neutropenia

A very difficult issue is how best to treat a patient who has
fever and neutropenia. Although detailed guidelines have
hematology/oncology
Table 8.
neutropenia
Fever and Neutropenia
ANC
1,000 to 1,500/mcL
(1.0 to 1.5109/L)
Mild
500 to 1,000/mcL
(0.5 to 1.0109/L)
Moderate
<500/mcL
(0.5109/L)
Severe
Etiology of Fever
Management
Outpatient/Hospital
Viral (frequent)
Supportive
Outpatient
Bacterial: URI
(sinusitis, purulent
rhinitis), otitis
media, local skin
infections
Indicated PO antibiotics
Outpatient
Bacterial pneumonia,
systemic
symptoms, GU
infections,
lymphadenitis
Blood cultures
Specific cultures
Best estimate
antibiotics
Observation for
progression
Supportive
Outpatient unless
progression
Bacterial: URI
(sinusitis, purulent
rhinitis), otitis
media, local skin
infections
Blood and other

cultures
Indicated PO or IV
antibiotics
Outpatient/Hospital*
Bacterial pneumonia,
systemic
symptoms, GU
infections,
lymphadenitis
Assume bacterial
Blood cultures
Specific cultures
Sepsis evaluation
Parenteral broadspectrum antibiotics
Blood cultures
Specific cultures
Sepsis evaluation
Parenteral broadspectrum antibiotics
Hospital
Viral
Outpatient
Hospital
ANCabsolute neutrophil count, GUgenitourinary, IVintravenous, POoral, URIupper respiratory tract infection.
*Either outpatient or hospital care may be appropriate for children who have moderate neutropenia and local infection, depending on the patients underlying
disorder and the anticipated time for recovery of the ANC. Children who have congenital/chronic neutropenia likely would benefit from treatment in the
hospital because recovery of the ANC is less likely without cytokine treatment. In contrast, neutropenia due to viral suppression, antibody effect, or some
medication exposures may allow a better response to localized bacterial infection and be managed on an outpatient basis.
been formulated for patients who have chemotherapyinduced neutropenia, relatively few data are available for
patients who have neutropenia not associated with cancer treatment. Fever is defined as a temperature greater
than 101F (38.3C) or a temperature of at least 100.4F
(38C) for longer than 1 hour. Most authors categorize
the severity of neutropenia into three groups (Table 8).
The decision surrounding treatment and potential hospitalization depends on the likelihood of bacterial infection, the location and severity of the infection, the severity of the neutropenia, and the likelihood and timeframe
of neutrophil recovery. Furthermore, the age of the
patient, the proximity of specialized medical care, and
the reliability of the guardians should be considered in
the management decision. Table 8 presents a starting
point for consideration of what to do and is based on
the principles used in the care of neutropenic chemother-
apy patients and the concerns of pediatric hematologists

and infectious disease specialists.
Specific recommendations for initial broad-spectrum
antibiotic coverage depend on the prevalence of organisms in each community and hospital and their susceptibility patterns. Approximately two thirds of isolated organisms are gram-positive (Table 9). Initial antibiotic
treatment may employ a single broad-spectrum antibiotic such as ceftazidime or cefepime. Alternatively, an
aminoglycoside can be combined with a beta-lactam
drug such as a third- or fourth-generation cephalosporin
for broad antibiotic coverage. The initial addition of
vancomycin is controversial, but should be done if resistant organisms are suspected because of their prevalence
in the community.
When to discontinue antibiotic treatment is a particular problem for physicians caring for patients who have
hematology/oncology
neutropenia
Bacterial Causes of
Febrile Episodes in
Neutropenic Patients
Table 9.
Aerobic Bacteria (90%)*

Gram-positive Cocci (45%)
Staphylococcus
Coagulase-positive (S aureus)
Coagulase-negative (S epidermidis and others)
Streptococcus
S pneumoniae
S pyrogenes
viridans group
Enterococcus faecalis/faecium
Gram-positive bacilli (rare)
Corynebacterium sp
Gram-negative Bacilli (45%)
Escherichia coli
Klebsiella sp
Pseudomonas aeruginosa
Anaerobic Bacteria (4% to 5%) (Often Polymicrobial)
Gram-positive Cocci (normal mouth flora)
Peptococci
Peptostreptococci
Gram-negative Bacilli
Bacteroides fragilis
Fusobacterium sp
*Percentages observed in patients receiving chemotherapy who were
immunocompromised (Mathur P, Chaudry R, Kumar L, Kapil A,
Dhawan B. A study of bacteremia in febrile neutropenic patients at a
tertiary-care hospital with special reference to anaerobes. Med Oncol.
2002;19:267272). Specific organisms were reported by Hughes WT,
Armstrong D, Bodey GP, et al. 1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America. Clin Infect Dis. 1997;25:551
573 and Merck & Co, Inc, Whitehouse Station, NJ, USA: 19952007
(http://www.merck.com/mmpe/sec14/ch178/ch178j.html).
neutropenia. If the blood cultures are negative and the

child becomes afebrile, antibiotics can be stopped, even if
the neutropenia persists. Usually, antibiotics are continued if the cultures are negative and the child remains
febrile and neutropenic. Fever generally resolves quickly
with antibiotic therapy if the neutropenia resolves. If the
cultures are positive and the child is no longer febrile and
neutropenic, the prescribed antibiotic treatment may be
completed with oral antibiotics at home. If the cultures
are positive and the child is afebrile but persistently
neutropenic, the course of antibiotics usually is completed in the hospital. The child then is observed for
24 to 48 hours prior to discharge. The persistence of
neutropenia requires the additional evaluation described
in this article and consideration of treatment with G-CSF
if the neutropenia is profound and there are frequent

infections.
The Medical Emergency of Fever With Severe

Neutropenia
Hospitalization is required for patients who have severe
neutropenia (specifically neutrophil counts less than
500/mcL [0.5109/L]), moderate neutropenia and severe infection, or any level of neutropenia combined with
ill appearance, as well as consultation with pediatric
hematology and pediatric infectious disease services. Patients who have immune neutropenia of infancy often
can be treated as outpatients because they can mobilize
neutrophils transiently. The hematologist can help establish the cause of the neutropenia, and the infectious
disease specialist can help identify the type and susceptibility of the infecting bacteria in the specific community.
If the patient is seen in the office, a blood culture (aerobic
and anaerobic) and a urinalysis and urine culture (no
catheter should be used) can be obtained and the initial
dose of antibiotics administered. If possible, an intravenous line should be kept open. The patient should be
transported to the hospital by ambulance because septic
shock may occur after administration of the first dose of
antibiotics.
On arrival at the emergency department, venous access should be ensured, and vital signs with oxygen
saturation, a CBC with differential count and platelet
count, and a metabolic profile should be obtained. No
rectal temperatures should be taken, rectal examinations
performed, or rectal medications administered because
of the risk of generating a perianal or perirectal infection.
However, careful examination of the mouth, oral mucosa, lungs, abdomen, and perineal/perianal area is important. A chest radiograph may be warranted if there are
respiratory signs or symptoms, but its usefulness may be
limited because the lack of neutrophils may not produce
a visible infiltrate in patients who have severe neutropenia.
Anticipatory Guidance for the Patient Who

Has Neutropenia
Parents of patients who have neutropenia need to contact
a health-care practitioner at the onset of any febrile illness
to assure prompt, appropriate care. The parents must
know what is required for the evaluation (including the
history and physical examination, blood counts and
ANC, blood and other cultures) and the initial treatment
(usual antibiotic recommendation and route of administration for their child) because they may not be near a
major medical center, particularly when traveling. A per-
hematology/oncology
mission form may be necessary to allow carrying of

injectable medications, such as G-CSF, syringes, and
hypodermic needles on airplanes. Parents should carry a
current written summary of the childs condition and
laboratory values and the contact numbers of their primary institution and physicians.
It is important to maintain good oral hygiene and
appropriate preventive dental visits, particularly for patients who have chronic neutropenia, to avoid chronic
gingival or dental infection. Good skin care and prompt
cleansing of superficial cuts, abrasions, and bruises where
the skin is broken help to prevent local infection. All
immunizations can and should be given according to
the routine vaccination schedule, as long as the patients neutropenia is not associated with an immunodeficiency syndrome. Children who have impaired T- or
B-lymphocyte function should not receive live or
attenuated-live vaccines. Recommendations for the administration of specific vaccines can be found in the
American Academy of Pediatrics Red Book and in the
Pink Book produced by the Centers for Disease Control and Prevention, Epidemiology and Prevention of
Vaccine-preventable Diseases.
Child care and school attendance are reasonable for
most children who have mild-to-moderate neutropenia,
although contact with obviously ill children should be
avoided. Children who have severe neutropenia or a
history of serious infections with neutropenia require
greater isolation to avoid exposure to infectious agents.
Genetic counseling for the family of patients who have
inherited neutropenias is indicated, and siblings should
be tested for the disorder. Families of patients who have
neutropenia may experience significant stress due to feeling responsible for the disease if it is an inherited condition or for exposing the child to infectious complications,
caring for a child who has a chronic illness, and managing
multiple physician and hospital visits. Most pediatric
hematology/oncology units have social workers, parent
advocates, and advanced-practice nurses who can provide the types of support services required by patients and
their parents.
Summary
Neutropenia unrelated to chemotherapy toxicity occurs
in a number of clinical settings. The most common
conditions associated with neutropenia are those that are
acquired, including viral infection, neutropenia associated with various medications, and immune neutropenia.
Inherited neutropenias are rarer and often more pro-
neutropenia
found. These disorders include the dominant or sporadic

types of severe congenital neutropenia (often with mutations in the ELA2 gene), the recessive type or Kostmann syndrome, and the marrow failure syndromes such
as Fanconi anemia. Cyclic neutropenia may be severe at
the nadir of the cycle. Of particular concern is the occurrence of fever in conjunction with neutropenia. This
combination creates a medical emergency that must be
addressed with appropriate evaluation and prompt administration of antibiotics. The actual risk of severe infection and the likelihood of recovery depend not only
on the level of the ANC, but on the duration of the
neutropenia. If recovery from the neutropenia is not
expected, as in severe congenital types, G-CSF administration may be indicated.
To view an additional Suggested Reading list and
figures related to this article, visit www.pedsinreview.
org and click on Neutropenia in Pediatric Practice.
Suggested Reading
Atallah E, Schiffer CA. Granulocyte transfusion. Curr Opin Hematol. 2006;13:45 49
Baehner RL. Drug-induced neutropenia and agranulocytosis. UpToDate. 2007. Available at: www.uptodate.com
Bertuch AA, Strother D. Fever in children with non-chemotherapyinduced neutropenia. UpToDate. 2007. Available at: www.uptodate.com
Bertuch AA, Strother D. Management of fever in children with
non-chemotherapy-induced neutropenia. UpToDate. 2007.
Available at: www.uptodate.com
Beutler E, West C. Hematologic differences between AfricanAmerican and whites: the roles of iron deficiency and alphathalassemia on hemoglobin levels and mean corpuscular volume. Blood. 2005;106:740 745
Boxer LA. Neutrophil abnormalities. Pediatr Rev. 2003;24:52 62
Boxer LA, Stein S, Buckley D, Bolyard AA, Dale DC. Strong
evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations. J Pediatr.
2006;148:633 636
Hughes WT, Armstrong D, Bodey GP, et al. 1997 guidelines for
the use of antimicrobial agents in neutropenia patients with
unexplained fever. Clin Infect Dis. 1997;25:551573
Klein C, Grudzien M, Appaswamy G, et al. HAX1 deficiency causes
autosomal recessive severe congenital neutropenia (Kostmann
disease). Nat Genet. 2007;39:86 92
Lehrnbecher T, Welte K. Haematopoietic growth factors in children with neutropenia. Br J Haematol. 2002;116:28 56
Palmblad JEW, von dem Borne AEG Jr. Idiopathic, immune,
infectious and idiosyncratic neutropenias. Semin Hematol.
2002;39:113120
Skokowa J, Germeshausen M, Zeidler C, Welte K. Severe congenital neutropenia: inheritance and pathophysiology. Curr Opin
Hematol. 2007;14:2228
hematology/oncology
neutropenia
PIR Quiz
Quiz also available online at www.pedsinreview.org.
6. A 6-year-old boy presents with a history of a temperature to 103F (39.4C) and ulcerations on his lips
and buccal mucosa 2 days ago. The child has some small, slightly ulcerated areas on his lips and is
afebrile. His mother reports two similar episodes in the past 2 months. He has a white blood cell count of
2.9103/mcL (2.9109/L), hemoglobin of 11.4 g/dL (114 g/L), and platelet count of 349103/mcL
(349109/L). His differential count is 40% neutrophils, 49% lymphocytes, 9% monocytes, and 2%
eosinophils. Of the following, the best laboratory test to evaluate this child is:
A.
B.
C.
D.
E.
Antineutrophil antibodies.
Blood counts two to three times a week for 4 to 6 weeks.
Bone marrow aspiration.
Herpes cultures.
Repeat of the count in 1 week to see if it normalizes.
7. A previously well 3-year-old boy presents with 4 days of temperature up to 104F (40C). He is in no
acute distress and does not appear ill. The only abnormal physical finding is mild rhinitis. A complete
blood count reveals a white blood cell count of 1.5103/mcL (1.5109/L), hemoglobin of 12.8 g/dL
(128 g/L), and platelet count of 349103/mcL (349109/L). His differential count is 2% neutrophils,
80% lymphocytes, 10% monocytes, and 6% eosinophils. A blood culture is obtained. After a single dose
of acetaminophen, the child becomes afebrile. Of the following, the most appropriate next step is to:
A.
B.
C.
D.
E.
Give a dose of broad-spectrum antibiotics and admit the child for continuing intravenous antibiotics.
Give a dose of ceftriaxone and see the child the following morning.
Observe the child in the emergency department overnight.
See the child the following morning but tell the parents to call sooner if he becomes more ill.
Start amoxicillin and clavulanic acid orally and see the child the following morning.
8. The mother of a well 4-month-old child would like you to obtain a complete blood count to make sure
her baby is OK. You determine that she has no specific anxieties or reasons for suspecting a problem. Of
the following, the most appropriate response is to:
A. Explain that a routine complete blood count is obtained at 9 months of age.
B. Explain that only a hemoglobin or hematocrit is measured routinely in well children at 9 to 12 months
of age.
C. Explain that there is no reason to obtain any blood counts for well children at any time.
D. Order a complete blood count.
E. Order a complete blood count with a differential white blood cell count.
9. What is the most common underlying cause for mild-to-moderate neutropenia?
A.
B.
C.
D.
E.
Exposure to medications such as antibiotics.

Immune neutropenia.
Shwachman-Diamond syndrome.
Sequestration.
Transient marrow suppression due to a viral infection.
10. At what age does alloimmune neutropenia usually resolve?

A.
B.
C.
D.
E.
2
2
5
2
6
to
to
to
to
to
3
3
6
3
7
days.
weeks.
weeks.
months.
months.
Index of Suspicion
Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S.
Bhende, Grace Pecson and Carolyn Leedy
Pediatr. Rev. 2008;29;25-30
DOI: 10.1542/pir.29-1-25
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/cgi/content/full/29/1/25
Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2008 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.
Downloaded from http://pedsinreview.aappublications.org at Health Internetwork on December 31, 2007
index of suspicion
Case 1 Presentation
The reader is encouraged to write

possible diagnoses for each case before
turning to the discussion. We invite
readers to contribute case
presentations and discussions.
Please inquire first by contacting Dr.
Nazarian at LFredN@aol.com.
Author Disclosure
Drs Hall, Friedland, Sundar, Torok,
Bhende, Pecson, and Leedy did not
disclose any financial relationships
relevant to these cases.
Frequently Used Abbreviations

alanine aminotransferase
aspartate aminotransferase
blood urea nitrogen
complete blood count
central nervous system
cerebrospinal fluid
computed tomography
electrocardiography
emergency department
electroencephalography
erythrocyte sedimentation
rate
GI:
gastrointestinal
GU: genitourinary
Hct: hematocrit
Hgb: hemoglobin
MRI: magnetic resonance imaging
WBC: white blood cell
ALT:
AST:
BUN:
CBC:
CNS:
CSF:
CT:
ECG:
ED:
EEG:
ESR:
A 12-year-old girl has had abdominal

pain for 3 hours. The pain developed
suddenly and is severe, sharp, constant, and located in the epigastrium
and lower quadrants, with no radiation. She has had five episodes of
bilious, nonbloody emesis. The pain
worsens with movement and vomiting, and she has found no way to
relieve it. Her last bowel movement
was yesterday and was normal. She
has had no fever, diarrhea, bloody
stools, or back pain. Past medical
history reveals intermittent constipation.
On physical examination, her
temperature is 96.3F (35.7C),
heart rate is 106 beats/min, respiratory rate is 14 breaths/min, and
blood pressure is 103/60 mm Hg.
Her abdomen is soft and slightly distended, with hypoactive bowel
sounds and both right and left lower
quadrant tenderness. Slight voluntary guarding is noted. The rest of
the physical findings are normal.
Her WBC is 9.6103/mcL
(9.6109/L), Hgb is 11.4 g/dL
(114 g/L), Hct is 33.3% (0.333),
and platelet count is 406103/mcL
(406109/L). Values for electrolytes, BUN, creatinine, liver enzymes, amylase, and lipase are within
normal limits; a pregnancy test is
negative.
Abdominal/pelvic CT scan with
intravenous contrast reveals a moderate amount of free fluid around the
cecum; the appendix is not visible.
Pelvic and abdominal ultrasonography is read as normal, but the appendix is not visible.
Following intravenous hydration,
she experiences persistent bilious
vomiting and abdominal pain and
undergoes a diagnostic laparoscopy,
which is converted to an exploratory
laparotomy when no colon is located
on the right side of her abdomen.
The cause of her pain and vomiting is

revealed at surgery.
Case 2 Presentation
A 14-year-old girl is seen in the ED
because of 2 days of lower abdominal
and back pain. The pain is a constant,
dull, bandlike ache of 9/10 in intensity. She denies fever, nausea, vomiting, diarrhea, melena, hematochezia,
dysuria, hematuria, vaginal discharge, or constitutional symptoms.
She is premenarchal and denies sexual activity.
She had an appendectomy at age 5
years complicated by the development of necrotic bowel, requiring a
small bowel resection. After recovering from surgery, she developed
chronic intermittent abdominal pain,
ultimately diagnosed as being functional. She describes her current pain
as different from her chronic abdominal pain.
On physical examination, the girl
is uncomfortable but in no apparent
distress and looks healthy. All vital
signs are normal. Her breast development is at Sexual Maturity Rating 5.
She is thin and easy to examine. Her
back is straight, with no tenderness
to palpation over the spine, paraspinal muscles, or costovertebral angles.
Her abdominal examination reveals a
10-cm linear, well-healed vertical
scar down the midline and a slightly
protuberant lower abdomen. Palpation reveals a large, well-defined, firm
mass extending from the pelvis halfway to the umbilicus in the mid-line.
Mild pain is elicited on deep palpation of the left lower quadrant, with
no guarding or rebound tenderness.
Additional examination reveals the
diagnosis.
Case 3 Presentation
A 6-month-old boy is readmitted because of respiratory distress and hypPediatrics in Review Vol.29 No.1 January 2008 25
index of suspicion
oxia 1 day after a 2-week hospitalization for bronchiolitis with hypoxia.

Despite resolution of signs of a respiratory tract infection, he was difficult
to wean from supplemental oxygen,
having percutaneous oxygen saturations of 88% to 92% in room air. He
was discharged after his percutaneous oxygen saturations remained at
90% to 96% for 24 hours in room air.
He was a small-for-gestational age
neonate, born via caesarean section
at 36 weeks gestation for maternal
double uterus, and remained in the
neonatal intensive care unit for
2 weeks for feeding and weight gain.
He did not receive any mechanical
ventilation, and his growth and development have been normal.
On physical examination, the patients weight is in the 10th percentile, height is in the 5th percentile,
and head circumference is below the
3rd percentile. His blood pressure,
heart rate, and respiratory rate are
normal. Percutaneous oxygen saturations in room air are 91%. He is receiving 2 L of supplemental oxygen
by nasal cannula and has no respiratory distress. Wheezing is audible bilaterally, and there is no heart murmur. He has a left facial nerve palsy
present since birth. Adequate perfusion and palpable pulses are noted in
all extremities. The remaining physical findings are normal.
A chest radiograph reveals multifocal atelectasis, a left-sided aortic
arch, and a cardiac silhouette that
measures at the upper limit of normal. Additional evaluation reveals
the diagnosis.
Case 1 Discussion
At laparotomy, intestinal malrotation
with small bowel obstruction at the
level of the distal ileum was found.
The Condition
Intestinal malrotation is an anatomic
anomaly caused by arrest of normal
rotation and mesenteric fixation of
the embryonic gut, a failure of normal embryologic gut formation that
occurs between the 5th and 10th
weeks of gestation. The result of a
nonrotated gut is location of the colon on the left side and a narrowbased mesentery in the upper midabdomen that is fixed to the right
abdominal wall by adhesions known
as Ladd bands. Anomalies commonly
associated with intestinal malrotation
include duodenal atresia (50%) and
jejunal atresia (33%). Disorders of intestinal rotation and mesenteric fixation to the posterior abdominal cavity are also common in infants and
children who have congenital diaphragmatic hernia, gastroschisis, and
omphalocele.
Intestinal malrotation is believed
to occur in 1 per 200 to 1 per 500 live
births, with symptomatic malrotation occurring in 1 per 6,000 live
births. Symptomatic malrotation is
evident clinically in the first postnatal
month in 64% of patients, and 82%
are diagnosed in the first postnatal
year; 18% to 25% of symptomatic patients are diagnosed at 1 year of age
and older. Because malrotation is discovered incidentally in some patients, the true number of patients
who have malrotation that is never
detected can only be estimated.
Malrotation can cause duodenal
obstruction because of impingement
on the bowel by the Ladd bands. The
most serious consequence is a midgut volvulus, a life-threatening condition in which the intestine twists on
the mesenteric stalk and compromises its blood supply, which can
lead rapidly to infarction of the entire
small bowel. Both duodenal obstruction from Ladd bands and volvulus
may occur intermittently, characterized by chronic and sometimes vague
complaints of abdominal pain with or

without vomiting.
Symptomatic malrotation with
volvulus presents as duodenal obstruction. In infancy, the clinical picture includes bilious emesis, abdominal pain, diffuse tenderness, and
bloody stool. Some clinicians warn
that the cause of bilious vomiting in a
neonate should be considered mechanical intestinal obstruction until
proven otherwise. Older children
and adults can present with acute or
chronic symptoms. Acute symptoms
include bilious vomiting, diffuse abdominal pain, and bloody stool.
Among the chronic symptoms are
intermittent vomiting and abdominal pain, constipation, malabsorption
syndrome, chronic diarrhea due to
protein-losing enteropathy, and failure to thrive. Older children and
adults who have chronic symptoms
may have received a previous diagnosis of irritable bowel syndrome or
cyclic vomiting. Some individuals
who are diagnosed later in childhood
are believed to have been experiencing intermittent, self-resolving volvulus.
Differential Diagnosis
The differential diagnosis for intestinal malrotation varies according to
the age of presentation. In infancy
and childhood, conditions to consider include necrotizing enterocolitis, pyloric stenosis, intussusception,
ileus due to sepsis or meconium,
Hirschsprung disease, appendicitis,
and duodenal atresia. In older children and adults, similar symptoms
can result from inflammatory bowel
syndrome, pancreatitis, or acute abdominal conditions such as appendicitis.
Diagnosis
Diagnostic evaluation generally requires a degree of suspicion for volvulus and, in a stable patient, can
index of suspicion
include abdominal radiography,

upper GI radiographic series, or abdominal CT scan. Adjunctive imaging techniques are abdominal ultrasonography and barium enema.
Radiographs often reveal a gasless
colon with a double-bubble sign
due to duodenal obstruction. An abdominal radiograph was not performed in this patient because appendicitis was believed to be likely, and
abdominal radiography would not
have been an optimal study for appendicitis.
An upper GI contrast study usually is considered the imaging study
of choice in a stable patient suspected
of having intestinal malrotation complicated by volvulus. An upper GI
radiographic series reveals failure of
the duodenal-jejunal junction to
cross the midline and a corkscrew
appearance of volvulus at the level of
the duodenum. CT scan may reveal
duodenal obstruction (in the case of
mid-gut volvulus) or appear normal
in the absence of volvulus. Ultrasonographic findings suggestive of
volvulus include identification of the
superior mesenteric vein on the left
rather than the right.
procedure, and Doppler ultrasonography at the time of surgery showed

normal blood flow to the distal ileum. Postoperatively, she developed
pancreatitis, which resolved after approximately 1 week of bowel rest and
fluid resuscitation. She was discharged with no additional complications.
Lessons for the Clinician

Most symptomatic cases of malrotation occur during infancy and usually
present with bilious vomiting. Fewer
cases present after infancy and have
varied presentations related to intermittent volvulus, with symptoms
that include abdominal pain, vomiting, and diarrhea. Volvulus can
mimic an acute abdominal inflammatory process, and diagnosis requires a
high degree of suspicion because
progressive intestinal ischemia may
become life-threatening. Patients
who present after infancy usually
have a history of chronic abdominal
complaints. (Cherilyn Hall, MD,
Allen Friedland, MD, Sumathi
Sundar, MD, Christiana Care
Health System, Newark, Del.)
Therapy
Intestinal malrotation requires surgical intervention. The Ladd procedure is recommended for intestinal
malrotation regardless of age or
symptoms. This operation includes
lysis of adhesions, widening of the
mesenteric base, and positioning of
the bowel in a place of nonrotation as
well as appendectomy and resection
of any necrotic bowel. The urgency
of the operation is dictated by the
presence of intestinal ischemia
caused by volvulus. In the setting of
malrotation without volvulus, most
surgeons advocate the Ladd procedure as a prophylactic maneuver to
reduce the probability of volvulus.
This patient underwent a Ladd
Case 2 Discussion
Examination of the patients genitalia revealed a normal vulva and labia
with Sexual Maturity Rating 5 distribution of pubic hair. A bulging, bluish membrane that was firm to palpation protruded from the introitus
(Figure). Abdominal and pelvic ultrasonography performed to confirm
the diagnosis of imperforate hymen
revealed a grossly dilated vagina filled
with homogeneous, echogenic material consistent with hematocolpos.
No other urogenital abnormalities
were present. The patient was admitted for a hymenectomy and evacuation of retained clotted blood. After
an uncomplicated hymenectomy, the
patient was discharged in good condition with relief of pain.
The Condition
Imperforate hymen is the most common obstructive genital tract anomaly occurring in females, having an
incidence of 1 in 1,000 to 1 in
10,000 individuals. Most commonly,
imperforate hymen is detected during adolescence either during an
evaluation for asymptomatic primary
amenorrhea or an investigation of
abdominal, back, or pelvic pain in the
premenarchal female. Other complaints include urinary retention and
pain with defecation. The pain is due
to the collection of menstrual blood
in the vagina and uterus. An imperforate hymen also can be detected on
prenatal ultrasonography as hydrocolpos if it is associated with urinary
obstruction and a urogenital fistula,
during a newborn examination as a
mucocolpos from maternal estrogeninduced secretions, or during a
health supervision visit as a membrane that bulges when the child performs a Valsalva maneuver. The term
hydrometrocolpos is used when both
vagina and uterus are dilated with
fluid.
Imperforate hymen is a sporadic
congenital outflow obstruction
anomaly resulting from the failure of
canalization of the tissue joining the
mullerian ducts and the urogenital
sinus during development. Embryologically, the female genital tract involves the medial migration and midline (horizontal) fusion of the paired
mullerian (paramesonephric) ducts
to form the uterus, cervix, and upper
vagina and the vertical fusion of the
developing ductal system with the
invaginating urogenital sinus to form
the lower vagina and introitus. Horizontal fusion defects result in vaginal
agenesis (also known as mullerian
agenesis
or
Mayer-RokitanskyKuster-Hauser syndrome) and may
index of suspicion
Figure. External genitalia showing bulging hymeneal membrane.
have associated urinary system abnormalities. Failure of vertical fusion

results in low obstruction abnormalities, such as imperforate hymen,
transverse vaginal septum, and cervical atresia, which usually are not associated with urinary abnormalities.
All of the previously noted conditions result in an accumulation of
menstrual fluid above the level of
obstruction.
The ovarian structures are derived
from a separate embryologic source,
the genital ridge. Therefore, ovarian
hormonal and endocrinologic function is normal in patients who have
genital outflow tract abnormalities,
which causes an apparent discrepancy
between physical findings of advanced secondary sexual characteristics and lack of menses.
An imperforate hymen is diagnosed by genital examination, which
reveals a translucent thin membrane
inferior to the urethral meatus that
bulges when the patient performs the
Valsalva maneuver. If hematocolpos
is present, a bluish discoloration is
apparent behind the membrane. The
volume of blood that collects can be

great enough to fill and distend the
uterus (hematometra), which may
present as an abdominal or pelvic
mass. Prolonged menses in a girl who
has an imperforate hymen may lead
to hematosalpinges and retrograde
menses into the abdomen, which
may cause intra-abdominal endometriosis and adhesions.
Differential Diagnosis
Although an imperforate hymen
should be obvious on physical examination, several conditions may
present with similar complaints and
findings. A history of primary amenorrhea in the presence of a blind or
absent vagina indicates a variety of
developmental anomalies of the genital outflow tract, including imperforate hymen, low-lying transverse vaginal septum, cervical atresia, vaginal
(mullerian) agenesis, and androgen
insensitivity syndrome (AIH). Of
these conditions, imperforate hymen, transverse septum, and cervical
atresia commonly present at the expected time of menarche in a girl
who has well-developed secondary

sexual characteristics and the complaint of cyclical lower abdominal,
back, or pelvic pain. On examination,
imperforate hymen appears typically
as a thin, bulging blue membrane;
transverse septa and cervical atresia
can be associated with a normal vaginal opening but shortened vaginal
canal. Ultrasonography can help
evaluate the level and volume of sequestered menses; MRI provides superior anatomic detail to define the
nature of anomalies further, including those of the upper urinary tract.
Only in rare instances is laparoscopy
required to clarify an anatomic developmental anomaly.
Vaginal (mullerian) agenesis and
AIH usually are asymptomatic presentations of primary amenorrhea associated with a vaginal anomaly. Patients born with vaginal agenesis
experience variable uterine development, with only 2% to 7% having a
uterus that has a functioning endometrium. This group may present
with cyclic or chronic abdominopelvic pain due to hematometra, but this
clinical picture is the exception.
Extragenital anomalies are common in vaginal agenesis and should
be screened for, particularly urologic
(30%) and skeletal (15%) abnormalities. AIH differs from the other mentioned anomalies in that it is a genetic
disorder of a chromosomal male
(XY) but phenotypic female due to
an androgen receptor mutation causing androgen insensitivity in the tissues and resulting in a blind vagina,
absent uterus, and testes in the inguinal canal. Imaging, along with evaluation of karyotype and hormone concentrations, further delineates this
disorder.
Treatment
Hymenectomy is the definitive treatment for an imperforate hymen.
Abdominal ultrasonography is rec-
index of suspicion
ommended before surgery to demonstrate that the true diagnosis is not

an obstructing transverse septum or
other genital anomaly. If abnormalities are present, the condition may be
more complex than a simple imperforate hymen, and surgery should be
delayed until the appropriate evaluation is performed, including MRI of
the abdomen and pelvis.
Surgical treatment of an imperforate hymen is not an emergency procedure. If a preadolescent is found to
have an imperforate hymen on examination but otherwise is asymptomatic, surgery often is delayed until
puberty to allow the hymen to become estrogenized, optimizing the
surgical outcome. A more urgent
hymenectomy is needed if the patient
also has urinary obstruction.
In addition to hymenectomy,
treatment for an imperforate hymen consists of evacuating copious
amounts of retained blood products and suturing the vaginal epithelium to the hymeneal ring. The
outcome of imperforate hymen
treated with hymenectomy is excellent. Follow-up in patients who
have had imperforate hymen
treated has shown normal pregnancy rates and sexual function.
Gynecologists have observed that if
endometriosis develops from retrograde menses, it is more likely to
resolve and have no significant effect on fertility compared with
spontaneous endometriosis occurring in the general population.
vanced breast development and lack

of menses did not correlate and, in
the presence of recurring abdominal
and back pain, led to the suspicion of
imperforate hymen. Imperforate hymen is the most common cause of
vaginal outflow obstruction, and surgical repair can relieve the obstruction and ensure commencement of
normal menses. (Kathryn S. Torok,
MD, Mananda S. Bhende, MD, Childrens Hospital of Pittsburgh, Pittsburgh, Pa.)
Case 3 Discussion
The baby continued to require supplemental oxygen and demonstrated
respiratory distress with feedings.
A video swallow study showed no
evidence of aspiration. CT scan of the
chest performed to evaluate pulmonary anatomic abnormalities as a
cause for prolonged hypoxia revealed
a vascular structure to the left of the
aorta consistent with a duplicated superior vena cava or anomalous pulmonary venous connection. An ECG
showed right atrial enlargement and
findings consistent with right ventricular hypertrophy. Echocardiography confirmed the diagnosis of unobstructed supracardiac total anomalous pulmonary venous connection
(TAPVC), with the pulmonary veins
draining into the innominate vein.
A large secundum atrial septal defect
(ASD) with right-to-left shunting
also was present.
The Condition
A teenage girl who has lower abdominal pain and back pain may bring to
mind an extensive differential diagnosis, leading to extensive laboratory
and radiologic testing. However, the
history and physical examination remain the most useful tools at the
physicians disposal to make the diagnosis. In this case, the patients ad-
TAPVC is a cyanotic heart defect that

represents approximately 1% to 3% of
all congenital heart defects. Males are
affected more often than females (4:
1). Some 33% of affected patients
have additional cardiac malformations, and 33% have other noncardiac
malformations.
TAPVC results from a developmental error that prevents a direct
communication of the pulmonary

veins to the left atrium. The pulmonary veins drain into the systemic venous system or directly into the right
atrium. In this malformation, an
obligatory right-to-left shunt nearly
always occurs at the atrial level. Formerly called total anomalous pulmonary venous return, the condition
more appropriately is called TAPVC.
The abnormality is the connection,
not the return, because the veins can
empty circuitously into the left
atrium or blood can flow into the left
atrium through an ASD.
The four types of TAPVC are based
on the location of the pulmonary vein
connection: supracardiac (50%, commonly into the left innominate vein or
right superior vena cava), cardiac (20%,
commonly into the coronary sinus),
infracardiac/subdiaphragmatic (20%,
commonly into the portal vein, ductus venosus, hepatic vein, or inferior
vena cava), and mixed (10%).
The presence of an obstructed
pulmonary venous connection affects
the clinical presentation. Typically,
tachypnea and cyanosis occur within
the first few days after birth as pulmonary blood flow increases. The obstructed flow causes pulmonary
edema and decreased lung compliance, which manifests as increased
work of breathing and hypoxia.
Feeding difficulties and other signs of
heart failure often are present. In addition, there is a fixed and widely split
second heart sound due to a delay in
pulmonary valve closure caused by
right ventricular volume overload.
Some infants also develop pulmonary
hypertension because of the obstruction.
Without obstruction, there may
be no symptoms at birth. However,
symptoms usually appear within the
first postnatal year. Signs may include
dyspnea on exertion and visible cyanosis with crying. Examination usually reveals a pulmonary murmur
index of suspicion
caused by increased flow across the

valve. The murmur may be difficult
to hear if there is pulmonary vein
obstruction. It can be distinguished
from pulmonic valve stenosis by the
absence of a pulmonary valve click.
An ASD causes a similar pulmonary
flow murmur and fixed splitting of
the second heart sound.
Rhonchi may be present in some
patients. As with this child, percutaneous oxygen saturations may be decreased only slightly because initial
pulmonary blood flow remains high
and a large interatrial connection allows oxygenated blood to flow into
the left atrium and systemic circulation. Progressive cyanosis results
from increasing pulmonary edema
that impairs oxygenation and decreasing right heart compliance that
increases the interatrial right-to-left
shunt. Both obstructed and unobstructed types can cause congestive
heart failure, growth restriction, and
multiple pulmonary infections.
Chest radiography may show an
enlarged heart with increased pulmonary flow, a snowman shape (in
supracardiac TAPVC), or an enlarged upper right heart border.
ECG shows right atrial and right ventricular enlargement. The diagnosis
is confirmed by identifying a pulmonary venous connection to the systemic veins, coronary sinus, or right
atrium on echocardiography.
Prognosis
Most patients who have TAPVC do
not survive beyond the first year
without surgery. Emergent surgery
may be necessary for neonates who

are in cardiogenic shock due to
TAPVC. Infants afflicted with infracardiac TAPVC die before 2 months
after birth without surgery. Advancements in surgical correction have
lowered mortality rates to near zero
and increased long-term survival to
98% at 7 years.
Cyanotic Heart Defects

Many nurseries routinely check percutaneous oxygen saturations at
birth. This screening is nearly 100%
specific in detection of cyanotic heart
defects. (1) Without screening and a
high level of suspicion, a subset of
patients born with congenital heart
disease will be missed. Patients who
manifest cyanotic heart disease outside of the neonatal period may
present with growth restriction or
failure to thrive, a history of recurrent
respiratory infections, mild or episodic cyanosis, or irritability.
As with this patient, persistent hypoxemia despite resolution of an infectious respiratory process is a major
sign of cyanotic heart disease. Indeed, many patients who have cyanotic congenital heart defects are
asymptomatic at birth because of the
presence of intracardiac mixing of
oxygenated and deoxygenated blood
that increases the arterial oxygen saturation. Infants born with hypoplastic left heart syndrome or left heart
obstruction or who experience increasing pulmonary blood flow as the
pulmonary vascular resistance falls
naturally (single ventricle without
pulmonary stenosis, large ventricular
septal defect) eventually show signs

and symptoms of heart failure or pulmonary edema. Unfortunately, for
those who have left heart obstruction, symptoms of heart failure may
be subtle and the phase of decompensation rapid.
Signs and symptoms of congestive
heart failure include irritability, poor
feeding, failure to thrive, tachypnea
without respiratory distress (happy
tachypnea) or tachypnea with respiratory distress due to pulmonary
edema or pleural effusion, and hepatomegaly. Any patient suspected of
having a cyanotic heart defect or congestive heart failure should be
screened with a chest radiograph and
ECG. Echocardiography provides
the definitive diagnosis.

Recognizing signs and symptoms of
cyanotic heart defects and early
symptoms of congestive heart failure
is critical to the early recognition,
management, and surgical correction
of these lesions. (Grace Pecson, MD,
Carolyn Leedy, MD, University of
Texas Southwestern Medical Center,
Childrens Medical Center, Dallas,
Tex.)
Reference
1. Reich JD, Miller S, Brogdon B, et al. The
use of pulse oximetry to detect congenital
heart disease. J Pediatr. 2003;142:268 272
To view Suggested Reading lists for

these cases, visit www.pedsinreview.org
and click on Index of Suspicion.
Index of Suspicion
Cherilyn Hall, Allen Friedland, Sumathi Sundar, Kathryn S. Torok, Mananda S.
Bhende, Grace Pecson and Carolyn Leedy
Pediatr. Rev. 2008;29;25-30
DOI: 10.1542/pir.29-1-25
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A Flood of Information
Lawrence F. Nazarian
Pediatr. Rev. 2008;29;3-4
DOI: 10.1542/pir.29-1-3
commentary
Commentary
Many elements in our lives can overwhelm us and overload our circuits,
including responsibilities, worries, and
conflicting appointments. Even some
treats we enjoy can get to be too much,
such as tomatoes in the garden at the
peak of the season, photographs waiting to be organized, and exceptional
books crying out to be read. Another
flood that threatens to engulf us is
information. Even if we ignore the obviously misleading or irrelevant rivers of
data flowing toward our minds, there is
enough worthwhile, relevant, desirable
information coming our way to sweep
us over the falls.
Restricting our focus to medical
knowledge, and even further to an understanding of pediatric medicine, we
still find that sector of the information
ocean stretching out to the horizon and
getting bigger every year. There used to
be lectures, seminars, workshops, textbooks, and journals. All of these sources
have multiplied, and we have added
continuing medical education courses,
teleconferences, CDs and DVDs, and
that infinite highway to knowledge
about everything under the sun and
beyond, the Internet. No wonder many
practitioners feel they are lost at sea
and going down for the third time.
Pediatrics in Review (PIR) and the
PREP program exist to throw you a life
preserver and a compass. Our primary
mission is to focus on the essentials of
pediatric medicine and to present current thinking about each aspect of that
body of knowledge to keep readers up
to date. We are fortunate to have
access to the content specifications of
the American Board of Pediatrics,
which has created a database that defines that core. In any given 5-year
period, PIR and the PREP SelfAssessment cover that content, allowing readers to refresh their knowledge
in a constant, renewing fashion. In the
process, steady readers are preparing
themselves for the cognitive testing
involved in maintenance of certification.
We continue to recruit our material
from the best teachers in our profession
and to spend countless hours making
what is written readable and lucid. The
individuals who produce PIR at all levels know what it is like to come home
after a long day and try to learn even
more. With that sensitivity, we attempt
to make our teaching as user-friendly
as we can.
Realizing that there are relevant and
interesting topics outside the core content, we have expanded our horizons,
adding two new sections in the last 2
years. Many parents are using or asking
about therapies outside of conventional
medicine, and we publish a regular
series on complementary and alternative treatments. As strong believers in
the role of pediatricians in the wider
community, we publish another regular
feature on community pediatrics that
highlights innovative and effective programs in that area.
Our electronic edition has allowed
us to broaden the spectrum of pediatric
subjects even further. By publishing one
or two articles each month in the
online-only format, we have created
new space to give our readers insights
into topics such as telemedicine, continuing medical education, and the
electronic medical record. The electronic capability has allowed us to provide recordings of heart murmurs as
well as still and moving pictures. The
online edition also allows for Rapid

Response, through which readers can
give us instant feedback on articles and
we can provide clarifications with equal
speed. We urge readers who are using
the online journal to click the Rapid
Response line every time they read an
article to see if there is any information
that has been added after publication.
Most clarifications are published in the
print edition as well, but with an inevitable lag time.
We have extended our reach beyond
our borders in several ways. Clinicians
in developing countries can access the
electronic version of the journal free of
charge. Authors from around the world
have contributed material, especially
through Index of Suspicion cases,
which have come from authors living in
22 countries. We have published a
commentary from Italy as part of an
article on evaluation of athletes, and
we hope to bring you more of these
perspectives. PIR has been published in
Chinese, Italian, Hungarian, Polish, and
Spanish, with a Turkish translation
starting up.
Residents rank among our most avid
readers, and we have a special relationship with these young physicians. Many
residents have written Index of Suspicion cases, and each year we choose a
case from their case-writing contest to
publish. Focus on Diagnosis, now in
its fourth year, is written exclusively by
residents, who share their knowledge of
cutting-edge diagnostic procedures. All
pediatric residents in the United States
receive a complementary subscription
to PIR, funded mainly by an unrestricted grant from Abbott Nutrition.
A great many people work hard to
make PIR what it is, and I would like to
commentary
acknowledge the contributions of Drs

Tina Cheng and Joseph Zenel, our invaluable Associate Editors; Drs Henry
Adam and Janet Serwint, who prepare
the In Brief articles; Dr Laura Ibsen,
who provides media of all kinds; and
our Medical Copy Editor Deb Kuhlman.
AAP staff members Luann Zanzola,
Susan Piscoran, Michael Held, and Dr
Robert Perelman give us constant sup-
port, as does our Editor Emeritus, Dr

Robert Haggerty. Our publishers, Cadmus and Highwire, create the final
product. The whole operation is held
together by Sydney Sutherland, our Editorial Assistant.
PIR is privileged to have an Editorial
Board of the finest pediatricians and
teachers available anywhere, and I extend to them my deep gratitude for the
countless hours they donate to make

this journal what it is.
Finally, thanks go out to our thousands of readers around the world. You,
and especially the children for whom
you care, are why we exist.
Lawrence F. Nazarian, MD
Editor-in-Chief
Lawrence F. Nazarian
Pediatr. Rev. 2008;29;3-4
DOI: 10.1542/pir.29-1-3
Updated Information
& Services


Reprints

Pediatrics in the Community: Community Pediatrics Training Initiative (CPTI)

Jeffrey Kaczorowski
Pediatr. Rev. 2008;29;31-32
DOI: 10.1542/pir.29-1-31
pediatrics in the community
Community Pediatrics Training

Initiative (CPTI)
Author Disclosure
Drs Kaczorowski and Aligne did not
relevant to this article.
Our inaugural story for Pediatrics in

the Community was in the January
2007 edition of Pediatrics in Review.
Dr Robert Haggerty provided the historical rationale for community pediatrics training (CPT) as part of that
feature. Now, 1 year later, we asked
Dr Jeff Kaczorowski, Director of the
CPTI at the American Academy of
Pediatrics (AAP), to describe the
present and future of CPT. As the stories in this series have shown, some residents are having wonderful community experiences already and making
a difference in the lives of children
in their communities. The challenge
is how to make such experiences available to all pediatric residents and
pediatricians.C. Andrew Aligne,
MD, MPH, Section Editor
home and school environments

where children spend their days. Programs that have these initial exposures often want to develop the next
level, particularly in the areas of
legislative/systems-level advocacy
and community projects.
CPTI is working on many fronts
with numerous partners to accomplish its mission of developing quality
CPT experiences at beginning, as
well as more advanced, levels. CPTI
is partnering with:
The CPTI was founded 8 years ago

by a remarkable pediatrician named
Anne Dyson, and in 2005, CPTI
moved to the AAP. Our ultimate
goal is to ensure that all pediatric
training programs develop and sustain quality community experiences
that are fully integrated into residency training. Maintaining a community perspective is a critical part of
what we need to do in pediatrics to
assure the health of all children in the
United States.
Residents and young pediatricians
across the country have told me that
they want this kind of training, and
national surveys confirm this significant demand. Residents understand
that community and environmental
factors play a major role in morbidities such as obesity, mental health
problems, child abuse, violence, and
injuries. Yet, many residency programs are just beginning to develop
training experiences that involve getting outside the hospital into the
the Ambulatory Pediatric Association to cosponsor the Pediatric

Academic Societies educational
scholars program for present or future faculty in academic pediatrics
who have an interest and experience in community pediatrics.
the AAP CATCH (Community
Access to Child Health) program
on grants for residency programs
to plan and implement community-based child health initiatives, as well as visiting professorships in community pediatrics.
the AAP Department of Federal
Affairs to support five facultyresident pairs annually to attend
the AAP Legislative Conference
and then to implement an educational activity on child advocacy in
coordination with their local AAP
chapter.
the AAP Council on Community
Pediatrics to sponsor the Pediatrics
for the 21st Century (Peds21) Symposium on Community
Pediatrics in October 2007, including a resident poster session
featuring community-based initiatives.
the AAP Division of State Government Affairs and Department of
Federal Affairs to develop an advoPediatrics in Review Vol.29 No.1 January 2008 31
pediatrics in the community
Figure. These children are participating in a program to help combat obesity and get children more active in Palo Alo, Calif. The
residents involved were Heather Iezza, MD, and Maria Mosquera, MD.
cacy guide for pediatricians, pediatric residents, and child health professionals, which will be available in
the spring of 2008.
Pediatrics in Review to sponsor this
feature.
CPTI has developed a number of

tools to support residency programs,
including the Community Pediatrics

Curriculum Manual (2005), the
Community-based Resident Projects
Toolkit (2005), and the CPTI Evaluation Toolkit (2007). CPTI will soon
launch a searchable online database
of community pediatrics training activities across the nation.
For more information on any of the
above or to join the CPTI listserv

to receive announcements about
grants and other opportunities, go
to: http://www.aap.org/commpeds/
cpti/or e-mail: cpti@aap.org.
Jeffrey Kaczorowski, MD
Director, CPTI
American Academy of Pediatrics
Pediatrics in the Community: Community Pediatrics Training Initiative (CPTI)

Jeffrey Kaczorowski
Pediatr. Rev. 2008;29;31-32
DOI: 10.1542/pir.29-1-31
Updated Information
& Services


Reprints

Inhalants
Michael Crocetti and Janet R. Serwint
Pediatr. Rev. 2008;29;33-34
DOI: 10.1542/pir.29-1-33
in brief
In Brief
Inhalants
Michael Crocetti, MD
Bayview Medical Center
Baltimore, Md.
Author Disclosure
Drs Crocetti and Serwint did not
relevant to this In Brief.
Recognition and Prevention of Inhalant

Abuse. Anderson CE, Loomis GA. Am
Fam Physician. 2003;68:869 874
Adolescent Abuse of Other Drugs.
Greene JP, Ahrendt D, Stafford EM.
Adolesc Med. 2006;17:283318
Inhalants of Abuse. Gussow LM. In: Ford
M, Delaney KA, Ling L, Erickson T,
eds. Clinical Toxicology. Philadelphia,
Pa: WB Saunders Co; 2001:651 656
Inhalant Abuse. National Institute on
Drug Abuse. Research Reports. http://
www.nida.nih.gov/ResearchReports/
Inhalants/Inhalants.html. Accessed
January 15, 2007
Inhalant Abuse and Dependence Among
Adolescents in the United States.
Wu L, Pilowsky DJ, Schlenger WE.
J Am Acad Child Adolesc Psychiatry.
2004;43:1206 1214
Inhalant Abuse. Williams JF, Storck M,
and the Committee on Substance
Abuse and Committee on Native
American Child Health. Pediatrics.
2007;119:1009 1017
Inhalants are volatile substances that,

when sniffed or snorted, can induce
euphoric and hallucinogenic effects.
These substances are lipid-soluble and
after inhalation are absorbed rapidly
through the lungs, quickly entering the
central nervous system (CNS). Inhalants
are classified as CNS depressants, but
acute intoxication can lead to a sense
of euphoria and excitability. Sniffing
involves inhaling vapors from an open

can or container, bagging describes
inhaling vapors that have been captured in a bag, and huffing consists of
inhaling volatile substances that have
been soaked in a cloth. Bagging and
huffing are preferred methods because
the user can inhale large concentrations of the drug.
Inhalant abuse reaches its peak between grades 7 and 9 in the United
States. Surveys of illicit drug use have
revealed that use of inhalants is second
to marijuana use among 8th and 10th
graders and that inhalants are the third
most widely used agents of abuse
among 12th graders. The Youth Risk
Behavior Survey 2005 reported that the
overall prevalence of lifetime inhalant
use was about 12%. Some studies suggest that females are as likely as males
to use inhalants prior to 17 years of age
but that males in the 18- to 25-year
age group are more likely to do so.
Rates of abuse have been reported to be
higher among American Indians,
whites, and Hispanics compared with
African Americans. Other research has
shown that a history of child abuse, a
history of being in foster care, poor
socioeconomic status, failing grades,
and dropping out of school are risk
factors associated with inhalant use.
Use of inhalants has been popular
for many years because these substances are inexpensive, legal, and easy
to obtain. Many can be found in common household products stored in garages, basements, and kitchens. Generally, there are four classes of inhalants.
Volatile solvents are liquids that vaporize at room temperature and can be
found in paint thinners, gasoline, and
glues. Aerosols include spray paints,
deodorant, and hair sprays. Gases can
be found in many commercial products.

Nitrous oxide is the most common
abused gas and can be found in butane
lighters, propane tanks, whipped cream
dispensers, and Freon. Nitrites, which
dilate blood vessels and relax muscles,
often are used as sexual enhancers.
These substances are prohibited by the
Consumer Product Safety Commission
but can be found in small bottles under
the names video head cleaner, room
deodorizer, or liquid aroma.
Inhalants produce a pleasurable effect by depressing the CNS in a manner
similar to that of alcohol. Research has
demonstrated that toluene, found in
glues, activates the brains dopamine
system. Acute effects of inhalant use
include excitation followed by drowsiness, disinhibition, lightheadedness,
and agitation. High doses may lead to
confusion and delirium. These acute
effects have a rapid onset but are
short-lived, and many adolescents inhale the substances repeatedly to gain
longer-lasting effects. Repeated use
makes the user vulnerable to the different stages of inhalant intoxication.
Stage 1 is the excitability stage,
stage 2 is the depressive phase, and
stage 3 is further depression of the
CNS. Stage 4 is the most worrisome
stage, in which CNS depression can
lead to coma, in addition to accidents
and trauma due to risk-taking behaviors. Up to 50% of inhalant-related
deaths are due to sudden sniffing death
syndrome. Inhalants sensitize myocardial cell membranes to depolarization,
and if the user is startled or engaging in
vigorous activity at the time, catecholamines are released, leading to
ventricular
fibrillation.
Inhalantassociated arrhythmias can occur after
a single inhalant use in otherwise
in brief
healthy adolescents. Sudden sniffing

death is associated most often with the
use of toluene, propane, butane, and
aerosols.
Diagnosing inhalant abuse is difficult and relies on a high degree of
suspicion, supported by a thorough history and physical examination. Other
causes of acute intoxication or altered
mental status should be considered,
such as hypoxia, hypoglycemia, ethanol,
illicit drugs, trauma, and infection. Inhaled hydrocarbons may be detected by
gas chromatography within 10 hours of
use, but this test is not readily available
at most medical facilities. Although not
specific, laboratory evaluation may reveal hypokalemia, hypophosphatemia,
hypocalcemia, metabolic acidosis, methemoglobinemia, and carbon monoxide
toxicity.
Laboratory evaluation should include a complete blood count, basic
metabolic panel, calcium and phosphorous measurements, hepatic panel, and
urinalysis for clues to inhalant use and
urine toxicology screen to detect other
illicit drug use. Consideration also
should be given to cardiac and muscle
enzyme analysis and electrocardiography, arterial blood gas determination to
rule out methemoglobinemia, and brain

imaging if neurologic signs are present.
Treatment of an acute overdose is supportive, with particular attention paid
to airway, breathing, and circulation.
Unfortunately, no medication can reverse the effects of most inhalants.
Long-term treatment of inhalant
dependence involves counseling, strict
abstinence, and drug treatment protocols such as 12-step programs and
inpatient and outpatient therapy. However, a recent survey found that many
centers are not adequately equipped to
treat inhalant abuse or dependence.
Comment: Dr Crocettis In Brief on
Inhalants is really thought-provoking.
He emphasizes the importance of considering inhalant use when evaluating
patients whose manifestations are either acute or chronic. Because inhalants are so easily available, they often
are used initially by younger, elementary school-age children; 3% of patients have tried inhalants by 4th grade.
Furthermore, those who reported first
use by 13 to 14 years of age were six
times more likely to become dependent
on inhalants than were those who began using at 15 to 17 years of age.
Signs of inhalant use may be subtle.

Clinicians need to be alert to odors on
the breath or clothes; discovery by parents of hidden empty cans; or signs of
slurred speech, nausea, and symptoms
similar to those of alcohol intoxication.
Chronic users may exhibit a huffers
rash, which is a dermatitis around the
mouth or nose, with cracking of the
skin and, sometimes, bacterial superinfection.
Because the effects of inhalants are
short in duration, it is unusual for
patients to seek medical attention unless they have developed chronic morbidity from long-term effects on the
brain, heart, lung, kidney, liver, or bone
marrow (suppression). Mortality can
occur both from the sudden sniffing
syndrome and through asphyxiation or
suffocation related to bagging or huffing. Education and prevention strategies for both children and their parents
must begin during elementary school to
minimize the morbidity and mortality
from this underdiagnosed form of drug
abuse.
Janet R. Serwint, MD
Consulting Editor
Inhalants
Michael Crocetti and Janet R. Serwint
Pediatr. Rev. 2008;29;33-34
DOI: 10.1542/pir.29-1-33
Updated Information
& Services


Reprints

Varicella-Zoster Virus Infections

Anne A. Gershon
Pediatr. Rev. 2008;29;5-11
DOI: 10.1542/pir.29-1-5
Article
infectious diseases

Anne A. Gershon, MD*
Author Disclosure
Dr Gershon has
disclosed that she
occasionally is a
consultant and
lecturer for Merck
Objectives
After completing this article, readers should be able to:
1. Describe the natural history and pathogenesis of varicella and zoster and how these
diseases are related.
2. Explain to patients and parents the complex role of this virus in causing disease and
how the virus spreads.
3. Describe how best to manage patients who have these infections.
4. Discuss how varicella vaccine works, how effective it is in preventing disease, and why
two doses of vaccine are now recommended.
and Company, Inc,

and GlaxoSmithKline.
The Pathogen
Varicella-zoster virus (VZV), a close but distinct relative of the other seven human
herpesviruses, including herpes simplex virus (HSV), causes two diseases. Varicella (chickenpox), a generalized illness, is its primary infection, and zoster (shingles) is its secondary
infection, caused by reactivation of VZV from latency. Varicella infection occurs in almost
all people over their lifetimes. VZV becomes latent after varicella and usually persists
silently and indefinitely. VZV reactivates, however, to cause zoster in roughly 20% of
individuals, with higher reactivation rates in immunocompromised patients and the
elderly.
Epidemiology
In the prevaccine era in the United States prior to 1995, approximately 4 million cases of
varicella and 1 million cases of zoster occurred annually. Varicella was primarily a disease of
children younger than age 10 years and zoster an illness of adulthood. Childhood varicella
infection, however, is less common than adult infection in countries that have tropical
climates. Varicella occurs in children who have no humoral or cellular immunity to VZV,
termed susceptibles. Zoster occurs in individuals who previously have had varicella; they
usually have detectable specific antibody titers, but have low or absent cell-mediated
immunity (CMI) to VZV.
VZV spreads primarily from the skin vesicles of persons who have varicella or zoster to
the respiratory tract of susceptible persons, who then become infected. Electron microscopic studies have shown a high concentration of well-formed, cell-free VZV in skin
vesicles. (1) Respiratory spread is difficult to rule out entirely, but during disease, it is rare
to isolate the virus from the throat, although it is common to isolate it from skin vesicles.
VZV spreads as cell-free enveloped viral particles, or virions, which are present in skin
vesicles and are small enough (approximately 200 nm in diameter) to be aerosolized. (2)
The virus spreads by the airborne route and requires direct exposure to an infected
individual for transmission.
Evidence for spread of VZV from skin is as follows. A 14% transmission rate of the
vaccine (Oka) strain of VZV occurred when susceptible siblings were exposed to a recently
immunized child who had leukemia and had a vaccine-associated rash. No transmission
occurred if the vaccinee had no rash, and VZV could not be isolated from the throats of any
of vaccinees, whether or not they had a vaccine-associated rash. Transmission rates were
directly proportional to the number of skin lesions. Recent observations in otherwise
healthy children who contracted wild-type breakthrough varicella after immunization also
have indicated that VZV spreads from skin. (3) Another recent study indicated that
*Professor of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY.
infectious diseases
varicella
children who had active varicella and were not excluded

from school on day 1 after rash onset played a major role
in spreading the virus in their classrooms. (4) Finally,
spread of VZV to observers during an autopsy indicates
that transmission by other means than the respiratory
tract must occur. (5)
VZV is highly communicable, and subclinical infection is unusual; clinical infection develops in about 80%
of susceptibles after family exposure. In contrast, in
healthy vaccinees, the Oka strain very rarely spreads to
others, even if a rash is present.
Patients who have zoster can transmit varicella to
others because the vesicular lesions contain infectious
VZV. About 100 years ago, during early attempts to
develop a VZV vaccine, children were inoculated with
vesicular fluid from zoster patients, and they developed
mild chickenpox. Zoster, however, is less contagious
than varicella.
The incubation period of varicella ranges from 10 to
23 days (average, 14 days). During the incubation period, VZV multiplies, spreads to regional lymph nodes,
and causes viremia. Wild-type VZV has been isolated
from blood cultures just before and during very early
chickenpox in immunocompetent children. An attractive, recently proposed pathogenetic mechanism is that
VZV reaches keratinocytes soon after infection by way of
VZV-infected CD4 memory T cells from infected tonsillar cells. These lymphocytes normally circulate through
the skin, engaged in immune surveillance; some also
become infected with VZV as they circulate, spreading
the virus in the body. In this model, overcoming innate
immunity in skin accounts for the 2- to 3-week incubation period following infection, as reviewed by Gershon
and associates. (6)
Second attacks of varicella are uncommon but may
occur. Asymptomatic immunologic boosting of VZV
immunity occurs after re-exposure to VZV in varicellaimmune individuals and may play a role in long-term
maintenance of immunity to VZV.
Patients who develop zoster usually have a history of
previous varicella. Zoster can occur in childhood; the
incidence is increased by a factor of as much as 20 in
those who had varicella in utero or before age 2 years,
possibly because the immune response to VZV in young
infants is immature. Infants afflicted with the congenital
varicella syndrome are at even greater risk for developing
zoster.
The incidence of zoster is age-related and begins to
increase sharply at 50 years of age. (7) Loss of VZV CMI,
which occurs during normal aging, is related to development of zoster. In keeping with this observation, zoster
can be prevented by immunization. Zoster also develops

commonly in patients treated for cancer and after organ
transplantation. Spinal trauma, irradiation, and corticosteroid therapy are other precipitating factors for zoster.
Children infected with human immunodeficiency virus
(HIV) are at increased risk for developing zoster. Children who develop zoster should be screened (usually by
history) for possible risk factors such as HIV infection
and underlying immunodeficiency; most often, however,
no predisposing factors are identified.
On occasion, zoster occurs in healthy children or
young adults. Presumably, such infection is the result of
a transient decrease in CMI to VZV, perhaps caused by
another inapparent viral infection. Low CMI to VZV is a
necessary, but not sufficient, requirement for the development of zoster.
The Diseases
Clinical Manifestations
Varicella usually is a mild-to-moderate illness in children.
It often is more severe in adults. Even in children, however, varicella cannot be counted on to be entirely benign. After a short or absent prodrome, skin lesions
appear. These start as macules and progress rapidly to
papules, vesicles, pustules, and scabs. The rash is concentrated on the trunk and head rather than on the extremities; it normally evolves as a series of successive crops
over 3 to 4 days. Most children have 250 to 500 superficial skin lesions, many of which are vesicular. Subclinical
elevations of hepatic transaminase concentrations are a
common, self-limited occurrence during varicella.
Zoster usually appears as a unilateral vesicular skin
eruption involving one to three dermatomes. Skin vesicles may be painful or pruritic, especially in adults. Zoster
generally is a milder disease in children than in adults.
From 25% to 50% of persons older than 50 years of age
and the same proportion of immunocompromised patients who acquire zoster experience serious pain, termed
post-herpetic neuralgia (PHN), after the rash has healed.
The cause of PHN is unknown.
Complications
The most common complication of varicella is bacterial
superinfection of the skin, lungs, or bones, most often by
Staphylococcus aureus or group A beta-hemolytic streptococci (GAS). Such infections may be severe and even
fatal. Whether treatment with ibuprofen is associated
with increased severity of GAS after varicella remains
unresolved. Therefore, this drug is not recommended for
treatment of fever accompanying varicella.
Central nervous system (CNS) complications, which
infectious diseases
may precede or follow varicella, include transient cerebellar ataxia, encephalitis, aseptic meningitis, and transverse myelitis. Most CNS complications are self-limited,
except for encephalitis, which frequently is associated
with severe sequelae if the patient survives. Other less
frequent complications of chickenpox include arthritis,
glomerulonephritis, myocarditis, and purpura fulminans.
Immunocompromised Patients
Varicella may be severe and even fatal in immunocompromised patients, particularly those who have malignancy or congenital deficits in CMI, as well as in those
who have undergone organ transplantation, have underlying HIV infection, or are receiving high doses of corticosteroids. Immunocompromised children who have severe varicella tend to have high fevers, extensive rashes
lasting for more than 1 week, hepatitis, and primary
viral pneumonia, which may be fatal despite antiviral
therapy. Children who have leukemia have a 30% rate of
disseminated varicella, with a 7% mortality rate. Severe
varicella may occur in HIV-infected children, especially
in those who have acquired immunodeficiency syndrome
(AIDS). In most of these children, however, mild-tomoderate varicella occurs, although the illness often is
more severe than occurs in healthy hosts.
Congenital and Neonatal Varicella

After maternal VZV infection in the first or second
trimester of pregnancy, approximately 2% of infants develop the congenital varicella syndrome. (8) Approximately 100 affected infants have been described since
1947; more than 95% of cases occurred after maternal
varicella and the remainder after possible maternal zoster. In the prevaccine era, an estimated 40 affected infants
were born annually in the United States. Cicatricial skin
scars (in 60% of cases) are the most prominent abnormalities. Other common manifestations include hypoplastic limbs, chorioretinitis, microphthalmos, Horner
syndrome, cataract, nystagmus, cortical atrophy or mental retardation, zoster, and early death.
Diagnosis
Chickenpox generally is diagnosed clinically because of
the characteristic vesicular rash and its distribution, as
well as through epidemiologic information such as history of exposure and absence of prior varicella. Zoster
also presents with a distinct unilateral, dermatomal, vesicular rash that is diagnosed clinically. Laboratory diagnosis can be used in questionable instances and is facilitated by the accessibility of the virus in superficial skin
lesions. (9) The diagnosis is made most definitively by
varicella
demonstration of specific viral antigens in skin scrapings

by immunofluorescence (DFA) using a commercial
monoclonal antibody to VZV conjugated to fluorescein
or by polymerase chain reaction (PCR). These diagnostic
methods are highly sensitive and rapid.
Diagnosis also may be made by isolating the virus
from skin lesions, but this technique is more complicated
and expensive, is less sensitive, and takes longer than
DFA or PCR. VZV rarely can be isolated from cerebrospinal fluid (CSF) and respiratory secretions. The presence of VZV or antigens in secretions or tissues is diagnostic of acute VZV infection because this virus is not
shed by asymptomatic persons. The Tzanck test is not
recommended by this author because it lacks sensitivity
and specificity.
Testing of skin scrapings, vesicular fluid, respiratory
secretions, and CSF by PCR is useful for diagnosing
VZV, and PCR is replacing culture in many laboratories.
PCR is available widely in commercial laboratories and
can distinguish between vaccine and wild-type VZV.
Many serologic tests measure antibodies to VZV,
including fluorescent antibody to membrane antigen,
latex agglutination, and enzyme-linked immunosorbent
assay (ELISA). Antibody to VZV develops rapidly after
the onset of varicella and persists indefinitely. Peak antibody concentrations occur after 4 to 8 weeks. VZV
infections may be proven by a fourfold or greater rise in
VZV antibody titer in acute and convalescent serum
specimens. Specific immunoglobulin M in one serum
specimen suggests recent VZV infection. Persistence of
VZV antibody in infants older than 8 months of age
suggests intrauterine varicella. Immunity to varicella is
highly likely if there is a positive antibody titer to VZV in
a single serum sample in a healthy patient. Commercial
ELISAs, however, usually are not sufficiently sensitive to
identify the level of immunity that develops in vaccinees.
After active immunization against VZV, antibody titers
are significantly lower than after natural infection.
Serologic procedures for diagnosing zoster are limited
because of the nonspecific increases in antibody titer
against VZV in some patients who have active HSV
infection. These viruses also share minor antigens, which
can lead to an increase in VZV titer with HSV infection.
Zoster occurs in the presence of serum VZV antibodies;
elevations in titer, therefore, can be missed.
CMI responses play the major role in host defense
against the virus. CMI to VZV can be demonstrated in
vitro most practically by stimulation of lymphocytes with
VZV antigens and by an interferon-gamma enzymelinked immunosorbent spot (ELISPOT) assay. CMI rePediatrics in Review Vol.29 No.1 January 2008 7
infectious diseases
varicella
actions remain positive for years, although CMI often

wanes in individuals older than 50 years of age.
Treatment
Nonspecific treatment for varicella includes oral antihistamines, frequent bathing, calamine lotion, oatmeal
baths, and the trimming of fingernails to discourage
scratching. Fever should be controlled with acetaminophen. Use of aspirin for this purpose may predispose to
Reye syndrome, and ibuprofen may predispose to GAS
infection.
Indications for Specific Treatment

Because most varicella infections are not serious and the
illness usually is self-limited in otherwise healthy children, oral acyclovir (ACV) is not administered routinely.
Further, the drug is not well absorbed from the gastrointestinal tract. Specific therapy is reserved for those at
higher risk for developing severe varicella or those who
already have severe disease. Because controlled studies in
children and adolescents given oral ACV for 5 days,
starting within 24 hours of the rash of varicella, have
shown a modest benefit, prompt oral ACV therapy usually is recommended for adolescents and young adults,
who are at moderately high risk for developing severe
illness. (10)(11)(12) The oral dose is 20 mg/kg qid for
children and 1 g qid for adolescents. The antiviral activity
of ACV depends on its phosphorylation by virus-induced
thymidine kinases.
Patients at serious risk for or who have severe or
potentially severe VZV infections should be treated with
intravenous (IV) ACV (10 mg/kg per dose tid for adults
and adolescents and 500 mg/m2 per dose tid for children). Patients whose creatinine clearance is less than
50 mL/min per 1.73 m2 are given one half to one third
of this dosage, with slow infusion, making sure that
hydration is adequate. ACV usually is tolerated very well,
but adverse effects include phlebitis, rash, nausea, and
neurologic symptoms. Children who are relatively immunocompromised, such as those who have early, seemingly mild varicella and those who have early HIV infection (not AIDS), may be given a closely monitored
treatment trial of oral ACV and switched to IV ACV if
clinically necessary. In those who have zoster, IV or oral
ACV heals skin lesions rapidly and resolves pain.
Development of drug resistance to ACV is of potential
concern. Resistance of VZV has been less of a problem
than with HSV; VZV resistant to ACV has been reported
only rarely. A vaccinated child who had neuroblastoma
and developed zoster due to the Oka strain that was
resistant to ACV after prolonged treatment has been

described.
Because data are few regarding the effectiveness of
ACV for preventing chickenpox in susceptible healthy
children, its use for this purpose is discouraged.
Famciclovir, an orally administered prodrug of ACV,
is converted to ACV in the body, with resulting higher
drug concentrations than oral ACV itself. Famciclovir is
administered three times a day for zoster (1,500 mg/d)
for adults but is not approved either for children or for
treatment of varicella. Another oral prodrug of ACV,
valacyclovir, achieves higher concentrations of ACV than
does famciclovir, but also is not licensed in the United
States for use in children or for varicella.
Foscarnet is used to treat VZV infections that are
resistant to ACV; the drug inhibits synthesis of VZV
DNA polymerase. The dose of IV foscarnet is
180 mg/kg per day divided into two doses, adjusted if
necessary for renal function. Toxicities include renal
damage and electrolyte imbalance.
Prevention
Control Measures
It virtually is impossible to protect susceptible individuals
from infection with VZV by avoidance because the agent
is highly communicable. Transmission is expected to
decrease, however, when VZV infection occurs in populations that are highly vaccinated.
Children who have chickenpox should be excluded
from school or child care from the time the diagnosis is
made until the lesions are crusted. Those who have zoster
may attend school if the lesions can be covered or when
they are crusted. The Table lists facts that can be helpful
in advising parents whose children are exposed to chickenpox. Patients who have active VZV infection and are
hospitalized should be isolated, preferably in a room that
has negative pressure ventilation, to minimize viral transmission.
Vaccination of individuals is particularly important if
there are family members who cannot be vaccinated,
such as a pregnant woman or immunocompromised
children. Transmission of the Oka strain from vaccinated
individuals, even if they develop a rash, is extremely rare
and has been reported after approximately 1 in 10 million
vaccinations.
Passive Immunization
Passive immunization is used to protect exposed highrisk persons from developing severe VZV. Treatment is
given to persons who have no history of previous VZV
disease, are at high risk for developing severe varicella,
infectious diseases
Information for Parents

Who Ask What to Do If Their
Child Is Exposed to
Chickenpox
Table.
1. Some 80% of children who received one dose of

vaccine are completely protected from chickenpox.
2. Only 3% to 4% of vaccinated children who received
one dose of vaccine develop full-blown chickenpox.
3. Breakthrough chickenpox is just as contagious as
chickenpox in unvaccinated children unless the child
has fewer than 50 skin lesions (very mild infection).
4. All children should receive two doses of vaccine; the
second dose can be administered as soon as 3
months after the first and even after an exposure
occurs, in which case it might offer additional
protection.
5. Rashes caused by the vaccine (Oka) strain (that
appear in weeks 2 through 6 after immunization)
can be infectious to others, but transmission is very
rare (roughly 1/10 million vaccines), and contact
cases uniformly are mild.
and have had an intimate exposure to VZV within the

preceding 5 days. Formerly, passive immunization was
accomplished by injection of varicella-zoster immune
globulin (VZIG). VZIG is no longer being produced,
however, because there was little demand for it after
1995. A similar product is available from Canada
(VariZIG, Cangene Corporation, Winnipeg, Canada)
and is recommended for neonates whose mothers have
active varicella at or soon after delivery and for exposed
susceptible high-risk patients. (13) The product is available in the United States under an investigational new
drug application expanded access protocol, with central
institutional review board approval. IV immune globulin
400 mg/kg is an alternative should neither VZIG nor
VariZIG be available. (13)(14)
Active Immunization
Live attenuated varicella vaccine was developed in Japan
in 1974. (15) Since 1995, universal immunization of
healthy children and adults in the United States who are
susceptible to varicella has been recommended by the
Centers for Disease Control and Prevention (CDC).
This vaccine is extremely safe and well-tolerated. About
5% of healthy children develop a mild rash approximately
4 to 6 weeks after immunization. Serious neurologic
events have not been related causally to varicella vaccine.
Vaccinees who develop VZV rash within 2 to 3 weeks
varicella
after immunization are likely to have wild-type infection

and should be regarded so.
Live attenuated varicella vaccine is highly effective in
healthy children and adults. Universal vaccination has
decreased the incidence, complications, morbidity, and
mortality of varicella by roughly 80% in the United
States.
Although varicella vaccine is highly effective, approximately 20% of children develop mild chickenpox after
exposure to wild VZV if they have received only one dose
of vaccine. Severe varicella occurs only in about 3% of
those who develop breakthrough varicella after vaccination. The vaccine is also 80% effective in adults after two
doses. Severe wild-type varicella in vaccinated adults is
rare. (6)(14)(16)(17)
It is unclear whether breakthrough varicella is the
result more from primary or secondary vaccine failure,
but primary vaccine failure seems to be the major factor.
Loss of VZV antibodies occurs rarely in healthy vaccinated children, even after a follow-up for as long as 20
years. Between years 1 and 8 after immunization, there
has not been a decrease in protection of healthy children.
There have been, however, numerous recent reports of
outbreaks of varicella among immunized children in
child care facilities and schools. Most investigations of
outbreaks have shown 80% to 85% vaccine effectiveness,
but some show effectiveness as low as 45% to 55%. (6)
(14) The children included in these studies had, for the
most part, received only one dose of vaccine.
A recent investigation indicated a significant degree of
primary vaccine failure (24%) in young children who
received only one dose of vaccine. (18) To decrease virus
transmission, improve vaccine effectiveness, and prevent
accumulation of susceptible young adults, two doses of
vaccinepreviously recommended only for those older
than 13 years of agewere recommended for all children
by the CDC in June 2006. Catch-up varicella vaccination
also is recommended for all children who received only
one dose of varicella vaccine in the past. After a second
dose of varicella vaccine, there is a marked boost in both
humoral and cellular immunity, and the second dose is
tolerated very well without significant complications.
One small study indicated improved protection after two
doses compared with one dose over 10 years of followup. (19)
Another important recent advance for varicella immunization was the development of the combined measlesmumps-rubella-varicella (MMRV) vaccine, which was
approved by the United States Food and Drug Administration in 2005. MMRV contains about 10 times the
amount of VZV as the monovalent formulation and is
infectious diseases
varicella
licensed only for children younger than 14 years of age.

Currently, most infants and children will be immunized
with two doses of MMRV after the shortage of this
vaccine is corrected. (20) Varicella vaccine also is recommended for susceptible adults, especially for healthcare workers and persons whose varicella-susceptible
family members are immunocompromised or pregnant.
Varicella vaccine is recommended only for healthy persons. Zoster appears to be less of a problem after immunization than after natural infection. The CDC now
recommends postexposure vaccination for healthy
varicella-susceptible exposed individuals.
Recently, a successful vaccine has been developed to
prevent zoster in older adults; this vaccine is the Oka
strain of VZV, given at a dose roughly 14 times greater
than that in the monovalent formulation. One dose of
this vaccine is recommended for healthy individuals older
than age 60 years who have had varicella but not zoster.
This vaccine is 50% to 60% protective against zoster and
its major complication, PHN. (7)
Summary
As a herpesvirus, VZV causes acute varicella, latent infection, and zoster. The virus has the potential to cause
serious infections, which may be difficult to treat. Complications include bacterial superinfections, CNS abnormalities, and a host of more unusual problems such as
pneumonia and hepatitis. Immunocompromised patients, pregnant women and their infants, and the elderly
are at highest risk of developing severe and even fatal
illnesses. In modern times, successful specific drug therapy has been developed. More recently, medical emphasis has been on prevention of illness by vaccination. Due
to the three-pronged approaches of passive immunization, active immunization, and antiviral therapy, the
morbidity and mortality from VZV infections have decreased impressively in the past 20 years. With continued
use and fine tuning of these modalities, particularly
active immunization, additional progress should be
made, resulting in the possibility of these infections
becoming unusual in the developed world.
References
1. Chen JJ, Zhu Z, Gershon AA, Gershon MD. Mannose
6-phosphate receptor dependence of varicella zoster virus infection
in vitro and in the epidermis during varicella and zoster. Cell.

2004;119:915926
2. Hambleton S, Gershon AA. Preventing varicella-zoster disease.
Clin Microbiol Rev. 2005;18:70 80
3. Seward JF, Zhang JX, Maupin TJ, Mascola L, Jumaan AO.
Contagiousness of varicella in vaccinated cases: a household contact
study. JAMA. 2004;292:704 708
4. Ma H, Fontaine R. Varicella outbreak among primary school
studentsBeijing, China, 2004. MMWR Morbid Mortal Wkly Rep.
2006;55(suppl 1):39 43
5. Paul N, Jacob ME. An outbreak of cadaver-acquired chickenpox
in a health care setting. Clin Infect Dis. 2006;43:599 601
6. Gershon A, Takahashi M, Seward J. Varicella vaccine. In: Plotkin S, Orenstein W, eds. Vaccines. 5th ed. Philadelphia, Pa: Saunders; 2008; in press
7. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent
herpes zoster and postherpetic neuralgia in older adults. N Engl
J Med. 2005;352:22712284
8. Gershon A. Chickenpox, Measles, and Mumps. 6th ed. Philadelphia, Pa: Saunders; 2006
9. Gershon A, Chen J, LaRussa P, Steinberg S. Varicella-zoster
virus. In: Murray PR, Baron E, Jorgensen J, Landry M, Pfaller M,
eds. Manual of Clinical Microbiology. 9th ed. Washington, DC:
ASM Press; 2007:15371548
10. Whitley RJ, Middlebrooks M, Gnann JW. Acyclovir: the past
ten years. Adv Exp Med Biol. 1990;278:243253
11. Balfour HH, Rotbart H, Feldman S, et al. Acyclovir treatment
of varicella in otherwise healthy adolescents. J Pediatr. 1992;120:
627 633
12. Dunkel L, Arvin A, Whitley R, et al. A controlled trial of oral
acyclovir for chickenpox in normal children. N Engl J Med. 1991;
325:1539 1544
13. Centers for Disease Control. A new product (VariZIG) for
postexposure prophylaxis of varicella available under an investigational new drug application expanded access protocol. MMWR
Morbid Mortal Wkly Rep. 2006;55:209 210
14. Centers for Disease Control. Prevention of varicella. MMWR
Morbid Mortal Wkly Rep. 2007;56:1 40
15. Takahashi M, Otsuka T, Okuno Y, Asano Y, Yazaki T, Isomura
S. Live vaccine used to prevent the spread of varicella in children in
hospital. Lancet. 1974;2:1288 1290
16. Vazquez M, LaRussa P, Gershon A, Steinberg S, Freudigman
K, Shapiro E. The effectiveness of the varicella vaccine in clinical
practice. N Engl J Med. 2001;344:955960
17. Vazquez M, LaRussa PS, Gershon AA, et al. Effectiveness over
time of varicella vaccine. JAMA. 2004;291:851 855
18. Michalik D, La Russa P, Steinberg S, Wright P, Edwards KM,
Gershon A. Primary immune failure after 1 dose of varicella vaccine
may be the main cause of breakthrough infections in healthy vaccinated children. J Infect Dis. 2008; in press
19. Kuter B, Matthews H, Shinefield H, et al. Ten year follow-up
of healthy children who received one or two injections of varicella
vaccine. Pediatr Infect Dis J. 2004;23:132137
20. Centers for Disease Control. Supply of vaccines containing
varicella-zoster virus. MMWR Morbid Mortal Wkly Rep. 2007;56:
146 147
infectious diseases
varicella
PIR Quiz
Quiz also available online at www.pedsinreview.org.
1. Infections of susceptible persons with the wild-type varicella-zoster virus (VZV) are transmitted primarily
through:
A.
B.
C.
D.
E.
Aerosols from skin lesions of infected individuals.

Direct contact with a skin vesicle that has a damaged mucosal surface.
Direct contact with a skin vesicle that has damaged skin.
Respiratory droplets from individuals who have skin lesions.
Respiratory droplets from subclinically infected individuals.
2. In a previously healthy 5-year-old child, the appearance of zoster most likely reflects a:
A.
B.
C.
D.
E.
Life-threatening defect in cellular immunity.

Life-threatening defect in humoral immunity.
Primary VZV vaccine failure.
Temporary phagocytic dysfunction.
Transient defect in cellular immunity.
3. A previously healthy 10-year-old boy develops uncomplicated varicella. As part of his initial management,
evidence-based practice supports the regular use of an appropriate dose of oral:
A.
B.
C.
D.
E.
Acetaminophen.
Acetylsalicylic acid.
Acyclovir.
Cephalexin.
Ibuprofen.
4. An 11-month-old girl who has acute lymphoblastic leukemia in early remission was inadvertently exposed
to varicella 1 day ago. To reduce the risk of life-threatening varicella, within 72 hours she should receive:
A.
B.
C.
D.
E.
An increase in her dose of prednisone.

Intravenous acyclovir.
Oral acyclovir.
Subcutaneous VZV vaccine (Oka strain).
VariZIG.
5. You are asked to speak with a group of medical students about varicella vaccine. Your most appropriate
statement is that after initial immunization:
A.
B.
C.
D.
E.
Breakthrough varicella generally is severe.

Neurologic complications remain a serious concern.
Primary vaccine failure is relatively common.
Transmission of attenuated virus is common.
Zoster incidence is unchanged.

Anne A. Gershon
Pediatr. Rev. 2008;29;5-11
DOI: 10.1542/pir.29-1-5
Updated Information
& Services


Reprints

Article
policy statements
American Academy of
Pediatrics Policy Statements
on Bioethics: Summaries and
Commentaries: Part 1
Mark R. Mercurio, MD,
Introduction
MA,* Mary B. Adam, MD,
The American Academy of Pediatrics (AAP) has a strong and longstanding interest in the
field of bioethics and periodically publishes policy statements pertaining to specific ethical
questions relevant to pediatrics. The subjects addressed cover a wide range of topics, from
parental refusal of immunization to the care of critically ill children. These policies are
authored initially by the AAPs Committee on Bioethics and undergo extensive internal
review by other committees prior to publication.
This article is the first in a series of three intended to familiarize readers with many of the
AAP policies currently in place that address issues in bioethics. In this series, 16 policies
published by the AAP are summarized, each followed by a brief commentary. The
commentaries are intended to address, at least on a cursory level, some of the ethical
principles underlying the policies. Some briefly point out possible alternative viewpoints.
The policies referenced in this article represent the efforts of various committees and
committee members over the years. Each of the summaries presented here, as well as the
commentaries that follow, represents the work of individuals serving on the Executive
Committee of the Section on Bioethics, as indicated at the beginning of each summary.
Understandably, some of the wording of these summaries is taken directly from the
published policies. When quotations are used within a summary and not referenced, it can
be assumed that the quote is taken directly from the policy being summarized. For ease of
use, the references for each policy are provided with each individual summary and
commentary.
MA,* Edwin N. Forman,

MD,* Rosalind Ekman
Ladd, PhD,* Lainie
Friedman Ross, MD, PhD,*
Tomas J. Silber, MD,
MAAS*
Author Disclosure
Drs Mercurio, Adam,
Forman, Ekman Ladd,
Friedman Ross, and
Silber did not disclose
any financial
relationships relevant
to this article.
Policies Reviewed
Part 1 of this series reviews:
1. Informed Consent, Parental Permission, and Assent in Pediatric Practice
2. Religious Objections to Medical Care
3. Responding to Parental Refusals of Immunization of Children
4. Sterilization of Minors With Developmental Disabilities
5. Human Embryo Research
6. Guidelines on Foregoing Life-sustaining Medical Treatment
7. Foregoing Life-sustaining Medical Treatment in Abused Children
8. Do-Not-Resuscitate Orders for Pediatric Patients Who Require Anesthesia and
Surgery
9. Do-Not-Resuscitate Orders in Schools
10. Ethical Issues with Genetic Testing in Pediatrics
11. Ethics and Care of Critically Ill Infants and Children
12. Female Genital Mutilation
13. Appropriate Boundaries in the Pediatrician-Family-Patient Relationship
14. Infants With Anencephaly as Organ Sources: Ethical Considerations
15. Palliative Care for Children
16. Institutional Ethics Committees
*On behalf of the American Academy of Pediatrics Section on Bioethics.

Pediatrics in Review Vol.29 No.1 January 2008 e1
policy statements
bioethics
Informed Consent, Parental Permission, and

Assent in Pediatric Practice
Committee on Bioethics. Informed consent, parental
permission, and assent in pediatric practice. Pediatrics.
1995;95:314 317. Available at: http://aappolicy.
aappublications.org/cgi/content/abstract/pediatrics%
3b95/2/314. Reaffirmed October 2006. Summary and
comment by Edwin N. Forman, MD, and Rosalind
Ekman Ladd, PhD.
Summary of Policy Statement

This statement comments on the concept of informed
consent and its application and limitations in the practice
of pediatrics, where a triad exists: physician, parent(s),
and patient. The policy analyzes the problematic issue of
who should make health-care decisions. It lays out the
elements and moral and legal underpinnings of informed
consent and consent by proxy (ie, by parents). The
concepts of emancipated and mature minors are presented.
The policy defines and defends the concept of assent.
Although children cannot be treated as rational, autonomous decision-makers, pediatricians should give serious
consideration to the patients developing capacities for
participating in decision-making. Children should be
involved in discussions about their health care, even in
situations in which one should not and does not solicit
their agreement to the proposed medical management.
Four elements of assent are emphasized: 1) helping the
child achieve a developmentally appropriate awareness of
the condition, 2) telling the child what should be expected with tests and treatment, 3) assessing the childs
understanding and factors that influence his or her response, and 4) soliciting an expression of the childs
willingness to accept the proposed care. The policy notes
that physicians and parents should not solicit childrens
views without intending to weigh them seriously. In
situations in which the medical treatment is deemed
essential and must be given despite the patients objection, the child should be told of this fact.
The AAP argues for shared decision-making, points
out limits on parental authority, and justifies the importance of involving the child in decision-making by noting
that such actions foster trust, create better physician/
patient relationships, and may improve long-term health
outcomes. Specific steps are outlined in obtaining assent,
depending on the patients developmental stage and the
medical situation, and in cases of conflict resolution.
Rejected are outright medical paternalism and total parental authority.
e2 Pediatrics in Review Vol.29 No.1 January 2008
Comment
This policy, which provides for a genuine form of child
assent, is based clearly on Western values. Modeled after
the informed consent requirement for competent adult
patients, it takes seriously an ethical duty to keep the
child informed in age-appropriate ways and to solicit an
expression of the childs willingness (ie, assent), when
appropriate, to undergo the proposed treatment.
The policy is somewhat unclear about when it is
appropriate to solicit assent. Dissent may be ethically
binding in the case of nontherapeutic research or nonessential treatment, but the policy notes that it is deceptive to ask for assent when treatment is necessary and the
childs dissent will be overridden. On the other hand, it
seems to recommend solicitation of the childs willingness to accept treatment, even when it is deemed essential
and only parental permission is required, as one element
of involving the child in discussions about his or her
health care.
Asking the child for assent recognizes the dignity and
moral status of the child. The model is to provide a
gradually increasing involvement of the child in making
choices as the child grows in competence and moves
from complete dependency on parents to independence.
However, in our pluralistic society, the ideal of an individual as independent and free-thinking is not accepted
by all cultural groups. Some cultures expect decisions to
be made exclusively by parents or elders, whatever the
age of the younger generation. In addition, the idea of a
school-age child expressing an opinion at variance with
his or her parents may constitute an upheaval of traditional values when the parenting style is authoritarian.
In using the AAP policy, the pediatrician is following
Western democratic values and should be sensitive to the
fact that some families come from cultures that have
different views of the role of the child.
Religious Objections to Medical Care

Committee on Bioethics. Religious objectives to medical care. Pediatrics. 1997;99:279 281. Available at:
http://aappolicy.aappublications.org/cgi/content/full/
pediatrics;99/2/279. Reaffirmed October 2006. Summary and comment by Mark R. Mercurio, MD, MA.

In this statement, the Committee on Bioethics, speaking
for the AAP, addresses parental decisions not to seek or
accept medical care for their children based on religious
objections. The major role that religion plays in the lives
of many adults and children in the United States is
recognized, and the need for the pediatrician to be
policy statements
sensitive to and have respect for religious tradition is

acknowledged. However, the AAP believes that all children deserve effective medical treatment that is likely to
prevent substantial harm or suffering or death, despite
religious objections that the parents may hold. If efforts
at collaborative decision-making with parents are not
successful in getting their approval for appropriate medical treatment in such cases, a court order ultimately
should be sought. If the childs life is in imminent
danger, the physician should intervene over parental
objections.
The AAPs position is consistent with that of the
United States Supreme Court. As the AAP notes: Constitutional guarantees of freedom of religion do not
permit children to be harmed through religious practices, nor do they allow religion to be a valid legal defense
when an individual harms or neglects a child. (1) The
AAP opposes exemption, based on religion, from child
abuse and neglect laws when children are not provided
necessary medical care. Failure to seek medical care when
a child is seriously ill should be considered child neglect,
regardless of the motivation. Laws that would allow an
exemption on religious grounds should be opposed or
repealed.
In the area of preventive care, a somewhat less forceful
stance is taken. Although the AAP strongly endorses
universal immunization, for example, it does not support the stringent application of medical neglect laws
when children do not receive those immunizations due
to parental refusal.
Comment
An ethical justification for the AAP position on this
matter could be presented as a rights-based argument.
Every child, it could be argued, has a right to medical
care that is likely to prevent substantial harm or suffering or death. The childs right creates obligations for
the parents, the physician, and society. The parents are
obligated to bring the child for the needed treatment,
which, in the opinion of the AAP, cannot be limited to
prayer or other spiritual practices alone but should include appropriate medical care.
The physicians responsibility is either to provide the
necessary treatment if able or to attempt to procure
appropriate medical treatment for the child. The policy
states that the physician may withdraw from these cases if
continuing would violate his or her own moral precepts,
after securing acceptable alternative care. However, a
practitioner willing to withhold medical treatment likely
to prevent substantial harm would not seem to qualify as
a provider of acceptable alternative medical care.
bioethics
Society is obligated to facilitate the provision of the

needed treatment to the child, including passing and
enforcing laws that support necessary treatment of children despite parental religious objections. However, it
could be argued, and rightly so, that society also is
obligated to protect religious freedom. The courts often
are asked to evaluate this tension between the parental
right to religious freedom (for themselves and their
children) and the childs right to necessary medical care.
In general, the courts have taken the position proffered
by the AAP: If the treatment in question is likely to
prevent substantial harm or suffering or death, the
childs right to treatment outweighs the parental right to
religious freedom. This viewpoint is not intended to
ignore the parents right to religious freedom, but rather
to recognize another right that should be given priority.
The choice of words within the AAP policy suggests,
however, that if prevention of substantial harm is possible
but perhaps not likely, the imperative to overrule parental
objection to treatment may be less certain. Again, the
courts often have held this position.
The policy alludes briefly to the concept of the mature
minor, including a recognition that as children grow into
adolescence, many have an increasing ability to contribute to or make their own medical decisions. In a previous
statement, the Committee on Bioethics opined that as
children develop, they should gradually become the primary guardians of personal health . . . assuming responsibility from their parents. (2) Based on that understanding, the policy at issue here states, in selected cases,
disputes may be avoided when a minor has the capacity to
make an independent decision in light of religious values
and recommended medical therapy. The pediatrician,
indeed, may perceive less dispute, and the right path may
seem clearer, when a mature minor requests a recommended treatment that his or her parents seek to refuse
on his or her behalf. However, what if the mature minor
refuses a lifesaving treatment, in accord with his or her
parents, based on religious objections? It is not clear what
the AAP would recommend in such a case.
A competent adults right to refuse treatment on
religious grounds is recognized widely. It is somewhat
unclear exactly when that right obtains, particularly if we
believe that the development of decision-making capacity is a gradual process. It seems reasonable to suggest,
nevertheless, that an individuals right to refuse medical
treatment on religious grounds should be recognized at
the same time as his or her right to refuse on any other
basis.
policy statements
bioethics
References
1. Walker v Superior Court, 763 P2d 852, 860 (Calif 1988), cert
denied. 1989; 491 US 905
2. Committee on Bioethics. American Academy of Pediatrics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics. 1995;95:314 317
Responding to Parental Refusals of

Immunizations
Diekema DS and the Committee on Bioethics. Responding to parental refusals of immunizations. Pediatrics.
2005;115:1428 1431. Available at: http://aappolicy.
aappublications.org/cgi/content/full/pediatrics;115/5/
1428. Summary and comment by Lainie Friedman Ross,
MD, PhD.

This statement begins with the AAPs strong endorsement of universal immunization, but acknowledges that
despite their safety and efficacy profiles, some vaccines
are refused by some parents. Some parents refuse because
of erroneous information; others refuse because of religious or philosophical beliefs. (1)(2) Data from a periodic survey of AAP members found that 7 of 10 pediatricians reported that they had a parent refuse an
immunization on behalf of a child in the 12 months
preceding the survey, (3) similar to other recent data. (4)
This statement recommends that when faced with a
refusal, physicians should try to: 1) understand the parents perspective, 2) correct any misinformation, and
3) encourage the parents to reconsider. It also asks the
physicians to consider whether the refusal exposes the
child to serious risk such that it constitutes medical
neglect and puts others at serious risk of harm, justifying
public health intervention. Because refusals rarely cause
imminent threats to a childs or a communitys health,
the AAP recommends that physicians respect the refusals.
The statement encourages physicians not to dismiss these
families but to continue to work with them to ensure that
their children have access to medical care and to maximize opportunities to encourage vaccinations.
Comment
This statement takes an ethical and pragmatic position:
Encourage universal immunization because that practice
serves the childs best interest and because it promotes
herd immunity (community benefit), but respect refusals. The authors acknowledge that immunizations are
neither 100% safe nor 100% effective but argue that the
benefit-to-harm calculation is extremely high and justifies universal immunization policies and practices. The
policy is clear that pediatricians generally should respect

families who refuse vaccines. The practice of respecting
parental refusals of vaccinations also is addressed in another AAP statement, Religious Objections to Medical
Care. This latter statement notes that some religious
groups deny children the benefits of routine preventive
care such as immunizations and states, [t]he AAP does
not support the stringent application of medical neglect
laws when children do not receive recommended immunizations. (5) This stance is consistent with an attitude
that intervention by the state should be invoked only
when it offers the least detrimental alternative. (6)
When most of the community is immunized, the risk to
the child is low, and state intervention cannot be justified, even though outbreaks do occur with attendant
serious consequences. (5)
With the development of new vaccines such as the
human papillomavirus vaccine and continued work on
human immunodeficiency virus vaccines, future policies
will need to consider whether these vaccines fit into our
current model of public health interventions and statemandated vaccination policies and how pediatric practices will be able to deliver vaccines that should be
provided to adolescents.
References
1. Salmon DA, Teret SP, MacIntyre CR, Salisbury D, Burgess MA,
Halsey NA. Compulsory vaccination and conscientious or philosophical exemptions: past, present, and future. Lancet. 2006;367:
436 442
2. Salmon DA, Moulton LH, Omer SB, DeHart MP, Stokley S,
Halsey NA. Factors associated with refusal of childhood vaccines
among parents of school-aged children: a case-control study. Arch
Pediatr Adolesc Med. 2005;159:470 476
3. American Academy of Pediatrics, Division of Health Policy
Research. Periodic Survey of Fellows No 48: Immunization Administration Practices. Elk Grove Village, Ill: American Academy of
Pediatrics; 2001
4. Flanagan-Klygis EA, Sharp L, Frader JE. Dismissing the family
who refuses vaccines: a study of pediatrician attitudes. Arch Pediatr
Adolesc Med. 2005;159:929 934
5. American Academy of Pediatrics Committee on Bioethics. Religious objections to medical care. Pediatrics. 1997;99:279 281
6. Goldstein J, Freud A, Solnit A. Before the Best Interests of the
Child. New York, NY: Free Press; 1979
Sterilization of Minors With Developmental

Disabilities
Committee on Bioethics. Sterilization of minors with
developmental disabilities. Pediatrics. 1999;104:337
340. Available at: http://pediatrics.aappublications.
org/cgi/content/full/104/2/337. Reaffirmed Octo-
policy statements
ber 2006. Summary and comment by Tomas J. Silber,

MD, MAAS.

This statement, reviewing the history of and considerations leading to the parental request of sterilization for a
son or daughter who has developmental disabilities, develops five recommendations, summarized as follows:
1. The AAP encourages pediatricians to use the development of secondary sexual characteristics in persons
who have developmental disabilities as an opportunity to
explore the patients and caregivers understandings of
the facts and implications of sexual maturation.
2. Consideration of sterilization should focus on
whether a need for permanent prevention of reproduction exists. Concern about other consequences of sexual
maturity or aspects of sexuality among persons who have
cognitive disabilities should focus on interventions substantially less radical than sterilization. The AAP encourages pediatricians to familiarize themselves with the resources in their community to which they might refer
families for additional information or for specialized education and counseling on such matters as appropriate
expressions of affection and sexual drives, effective menstrual hygiene, sexual abuse avoidance training, and contraception.
3. Whenever possible, pediatricians should involve
their patients who have developmental disabilities in
decisions about reproduction and should advocate for
the least permanent and intrusive method of contraception consistent with the lowest risk for the patient.
4. When a minor who has developmental disabilities
requests sterilization and an assessment determines that
the minor has adequate decision-making capacity to consent to the procedure, the minors views on the matter
should be respected. Such decisions generally benefit
from the involvement of the adolescents family, other
adults close to the adolescent, or both.
5. Pediatricians should become familiar with the applicable law about sterilization of persons who have
developmental disabilities. Pediatricians should establish
relations with local agencies and attorneys knowledgeable about the legal complexities of sterilization of persons who have developmental disabilities in their jurisdiction. If sterilization is legally permissible on the
authority of parents or legal guardians and is chosen as
the best course of action, substantial effort should be
made to communicate to the patient the facts and implications of the sterilization. To the extent possible, the
patient should participate in planning for the procedure.
bioethics
Comment
This policy statement updates a previous AAP statement
entitled, Women Who Are Mentally Handicapped,
published in 1990. That statement was published as a
companion to a policy of the American College of Obstetricians & Gynecologists. The revised policy is based
on concepts developed in the earlier statements, but now
applies them to both males and females. This is the policy
to consult whenever parents or legal guardians approach
pediatricians or other health-care professionals about the
possibility of surgical sterilization of children, adolescents, and young adults who have developmental disabilities.
Sterilization has a long history of abuse in the United
States. However, by the middle of the 20th century, the
United States Supreme Court prompted a major change
in the legal landscape by declaring human procreation a
fundamental right. Since then, requests for authorization
to sterilize those who have developmental disabilities
have been the object of scrutiny, limitations, and even
prohibition in many jurisdictions. In the 1970s, for example, regulations were enacted to prevent the use of
federal funds to perform sterilization procedures on
those deemed mentally incompetent. It should come as
no surprise that, at present, we face so many federal rules,
state laws, and judicial rulings that pediatricians whose
advice is requested find themselves facing a confusing
and contradictory array of restrictions on surgical sterilization of persons with development disabilities. Indeed, this confusion may not be a coincidence because an
ethical tension exists between the obligation to honor
the least restrictive alternatives for those who have cognitive disabilities and the concern about abuse and coercion leading to unwanted pregnancy or, worse, a pregnancy that the child may not comprehend or may be
terrified by. Moreover, those who love and care for
developmentally delayed children certainly may have
their best interest at heart when they know that those
individuals are not capable of caring for offspring.
Although this statement gives guidance on how to
proceed when sterilization becomes the choice, its major
strength is that it develops the fundamental criteria required to make that decision ethically permissible,
namely, that the person lacks adequate mental capacity to
make decisions about his or her health care and is unable
to interpret his or her own interests. Thus, there is a
moral mandate before sterilization can be considered:
Assessment of an individuals capacity to decide matters
specifically concerning reproduction and an obligation to
obtain help from professionals experienced with evaluatPediatrics in Review Vol.29 No.1 January 2008 e5
policy statements
bioethics
ing the capabilities of persons with disabilities. Once the

decision has been reached, the advocacy work starts.
Human Embryo Research

Committee on Bioethics and Committee on Pediatric
Research. Human embryo research. Pediatrics. 2001;
108:813 816.
Available
at:
http://aappolicy.
aappublications.org/cgi/content/full/pediatrics%3b108/
3/813. Reaffirmed January 2005. Summary and comment
by Mary B. Adam, MD, MA.

On behalf of the AAP, the AAP Committee on Bioethics,
and the AAP Committee on Pediatric Research wrote a
policy statement asserting, under certain conditions,
research involving human embryos and pluripotent stem
cells is of sufficient scientific importance that the National Institutes of Health should fund it and that federal
oversight is morally preferable to the current unregulated
private sector. According to the statement, embryos are
defined as human organisms derived by fertilization
from one or more gametes or diploid cells. (Embryos
formed using a diploid cell is a reference to cloning
human embryos.) Justification for use of human embryos
includes the possible identification of potential benefits
to children as a class as well as the more global potential
for medical benefits.
The statement acknowledges that its position is controversial because some believe that research using human embryos is morally problematic. Opponents to the
AAPs position object to the destruction of human embryos for research purposes because they view humans at
all stages of development as deserving full human value.
Those who object to the use of human embryos in
research concede that even if that research may have great
therapeutic potential, the ends do not justify the
means.
Ethical concerns also arise regarding how the embryos
are acquired for research and the possible moral complicity of researchers. The statement claims that using discarded embryos that are no longer needed by parents for
assisted reproduction (clinical need) is less problematic
than the creation of embryos for the specific purpose of
research. However, the use of embryos that are no longer
clinically needed as children for the couple using in vitro
fertilization techniques still can cause ethical problems
related to obtaining adequate informed consent from
donors, ensuring privacy of donors, and decreasing potential or perceived conflicts of interest by those who may
request the donation and concerns about undue financial
inducement to acquire embryos. These concerns are
addressed by recommending limiting human embryo

research to a set of eight conditions and suggesting a
group of considerations for obtaining informed consent
from donor parents. The eight recommended conditions
are:
1. The embryos are already frozen and no longer are
clinically needed.
2. A clear separation exists in the donor decision
process between the decision by the donors to create
embryos for infertility treatment and the decision to
donate frozen embryos for research purposes after they
are no longer clinically needed.
3. The decision to donate is strictly voluntary and
without monetary inducements.
4. The physician responsible for fertility treatments is
not to be the person performing the research on the same
frozen embryos, and there should be no monetary relationship, that is, transfer of funds in the research project
to the physician responsible for the fertility treatments.
5. There are to be no personal identifiers associated
with the embryos used for research.
6. No restrictions can be placed by the donor on the
type of research performed.
7. The research performed on the frozen embryos can
be of no direct benefit to the original donors.
8. The embryo research does not involve research in
reproductive cloning, transferring an altered embryo to a
womans uterus, or using a human embryo in combination with other human or animal embryos.
A unique status of the individual human embryo is
acknowledged, and the following limitations are proposed as safeguards: 1) research is to be limited to
embryos in the first 14 days after fertilization, and
2) funding and additional oversight at the federal level
are appropriate, including the creation of a new Department of Health and Human Services committee to oversee human embryo research specifically and develop ethical guidelines for its use.
Comment
The moral standing of the embryo has generated significant debate in the public sector, and this statement, not
surprisingly, created some controversy. Drs Chesney,
Botkin, and Nelson responded for the Committees on
Pediatric Research and Bioethics to a letter to the editor
of Pediatrics, stating, Given the fundamental disagreements over the moral status of embryos, it probably is
impossible to develop a position on this subject that all
would consider acceptable. (1) These fundamental disagreements are not scientific in origin because all parties
would agree that the human embryo is a being of human
policy statements
origin. The disagreement, rather, is the result of different

perspectives on the meaning and ramifications of protecting human value and dignity. Those who hold to a
view that the human embryo is deserving of full moral
respect point out that various criteria have been used
wrongly during different periods of human history to
identify beings of human origin not believed to be worthy of full human value, dignity, and respect. These
criteria have included: location, ethnicity, mental capacity, stage of development, and sex (especially female sex).
It is argued that a similar injustice is done when human
embryos are denied full protection because they are
members of the human community. To do so would
provide a toehold for other potential abuses of human
beings, a slippery slope argument. Those who hold
this view might agree that research has therapeutic potential but would say that the ends do not justify the
means.
On the other hand, the argument that the potential
for scientific progress outweighs morally problematic
concerns is a utilitarian perspective. Research on nonconsenting human embryos, for whom there is no prospect
of direct benefit and who would be destroyed in the
process, could be acceptable from a utilitarian view if the
potential gain for others might outweigh the concern.
A developmental perspective is another perspective that
may be consistent with permitting research on human
embryos. In this view, one would assign different levels of
moral status to human beings at different stages of development or capacity, with those individuals at the
earliest stages of development being accorded less moral
status (and, thus, more limited rights) than those later in
development.
The AAP recognizes the human embryo as unique, a
special tissue deserving of respect, but by allowing their
use in research up to 14 days after fertilization, places
embryos before 14 days of existence as having less moral
worth than individuals at later developmental stages.
This combining of a utilitarian and developmental perspective permits the AAP to encourage lifting restrictions
on federal funding for research on human embryos in
some limited circumstances when the embryo is early
enough in development, where potential benefit is seen,
and where additional oversight is included. The statement does not specifically address protections or oversight for embryos when the research is privately funded.
Other ethical issues in the statement flow out of a
value for the unique moral standing of the human
embryo. For example, the issue of the comodification of
human embryos is addressed. The Committee expresses
concern about the potential sale of human embryos and
bioethics
recommends that no embryo be offered for research with

monetary inducements on the part of the physician responsible for fertility treatments, donor parents, or researchers. This point of view is prudent because the sale
of human gametes for financial profit (via Internet and
newspaper advertisements) is widespread. This issue also
highlights the needs and challenges of oversight because
creating embryos is not illegal, and human gametes are
easily procured for cash.
The AAP statement identifies parents as the donors
who are entitled to represent the interests of the embryo.
Parents are required to give their consent to donate their
embryos for research. However, no statement is included
discussing if one or both parents must agree with the for
research designation. Concerns about the potential for
coercion of parents by researchers are part of the impetus
to recommend that the donation be strictly voluntary
and without monetary inducements.
The limitations on the use of human embryos in
research provided by the AAPs statement include a
prohibition on the use of embryos for reproductive cloning. There is no specific mention of the related research
issue of human therapeutic cloning. However, donor
consent in cases of therapeutic cloning would be problematic because there is no separation of the decision
process to create the embryo and to use the embryo for
research/therapeutic purposes (see recommendation 2).
The AAPs position was challenged in a letter to the
editor. (2) The response included the following statement: We feel that an ongoing debate on these topics is
meaningful, pertinent, appropriate, and a right of all
American citizens. (1) Given the call for meaningful
debate, this statement can be a launch point for discussions on what it means to be human. Do all beings of
human origin deserve full moral status, worth, and human dignity? If not, why not? If so, how does one justify
drawing a line on the continuum of human development? Where do we draw the line? How do we safeguard
against turning beings of human origin into commodities or parts for sale? Are humans worth more than the
sum of and sale of their parts? (3)(4)(5)
References
1. Committee on Bioethics and Committee on Pediatric Research.
Embryonic stem cell research. Pediatrics. 2002;109:990 991
2. June P. Embryonic stem cell research. Pediatrics. 2002;109:

990 991
3. Devolder K. Creating and sacrificing embryos for stem cells.

J Med Ethics. 2005;31:366 370
4. Cheshire WP. Human embryo research and the language of

moral uncertainty. Am J Bioethics. 2004;4:15
policy statements
bioethics
5. Cameron C, Williamson R. In the world of Dolly, when does a

human embryo acquire respect? J Med Ethics. 2005;31:215220
Conclusion
The AAP periodically publishes policy statements and
guidelines addressing difficult ethical issues that physicians caring for children will continue to face. This review
is intended to provide readers an overview of some of
those guidelines and possibly stimulate additional
thought and dialogue within the profession. It is presented by the AAP Section on Bioethics as part of its
mission to foster education in this area among pediatricians. As the commentaries suggest, there may not be
unanimity about the positions taken, which is important
to recognize. The full text of each policy, as well as other
relevant references and information, can be found on the
web site for the Section on Bioethics at http://
www.aap.org/sections/bioethics.
The Section on Bioethics serves primarily an educational role within the AAP and beyond. They organize
educational forums in bioethics at the annual AAP Na-
tional Conference and Exhibition, publish a newsletter

that includes original articles in the area of bioethics, and
carry out other educational efforts intended primarily for
pediatricians. In addition, they provide input to the
Board of Directors and other committees regarding proposed policy statements and guidelines. Membership in
the Section is open to all AAP Fellows who have an
interest in bioethics. Affiliate membership also is available
to physicians and other health professionals not eligible
for AAP membership.
This is the first in a series of three articles on AAP
policies that address ethical issues in pediatrics. The next
two articles will appear in subsequent issues of Pediatrics
in Review.
ACKNOWLEDGMENTS. The authors would like to
thank Marilyn A. Maxwell, MD, and Brenda Jean Mears,
MD, their colleagues on the AAP Section on Bioethics
Executive Committee, for guidance and helpful comments in the preparation of this manuscript.

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When to Order a CBC

Normal Values for the ANC and the Definition of Neutropenia

Normal Blood Leukocyte Counts*

(1.0109/L) between 2 weeks and 1 year of age, 1,500/

Pyogenic Infections Associated With

Initial Evaluation of the Patient Who Has

Initial Evaluation for

History of underlying disease, congenital anomalies,

Short stature, malnutrition, skeletal abnormalities

CBC With Differential Count and Reticulocyte

Confirm the finding of neutropenia, evaluate

Other Laboratory Tests

drome. Mouth ulcers may occur in association with

appears well. If the neutropenia persists or progresses

Detailed Laboratory Evaluation of Neutropenia

CBC and Differential Count

DNA Analysis (HAX1, ELA2, Gfil)

ation exists for drug-induced immune neutropenia. If the

trophil antibodies passively to the developing fetus. This

Viral marrow suppression or

EBV/parvovirus/HHV6 and other viruses

Antigen difference in newborn and

Consider also familial benign

Common if spleen is enlarged

Vitamin B12 or folic acid

EBVEpstein-Barr virus, HHVhuman herpesvirus, SLEsystemic lupus erythematosus.

per day administered orally in two divided doses, and the

severity of neutropenia, and the marrow findings are not

Partial List of Drugs Associated With Idiosyncratic Neutropenia

Inherited Neutropenia (Table 6)

Rare (1/1 to 200,000) ANC <500/mcL (0.5109/L)

Marrow Failure Syndromes:

WHIM Syndrome and

Gene (FANC) defects in 1/106

18 Pediatrics in Review Vol.29 No.1 January 2008

Inherited Neutropenia Continued

Selective IgA Deficiency

1/105 live births

TAZ mutation on the X Rare

Initially 5 mcg/kg per day subcutaneously

Marrow Failure Syndromes

DYSKERATOSIS CONGENITA (ZINSSER-ENGMAN-COLE

Syndromes Associated With Neutropenia and

Fever and Neutropenia

Fever and Neutropenia

Blood and other

apy patients and the concerns of pediatric hematologists

Aerobic Bacteria (90%)*

neutropenia. If the blood cultures are negative and the

if the neutropenia is profound and there are frequent

The Medical Emergency of Fever With Severe

Anticipatory Guidance for the Patient Who

mission form may be necessary to allow carrying of

found. These disorders include the dominant or sporadic

Pediatrics in Review Vol.29 No.1 January 2008 23

Exposure to medications such as antibiotics.

10. At what age does alloimmune neutropenia usually resolve?

24 Pediatrics in Review Vol.29 No.1 January 2008

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The reader is encouraged to write

Frequently Used Abbreviations